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Abstract Background Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Methods Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. Results In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. Conclusions This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.

Abstract When different researchers study the same research question using the same dataset they may obtain different and potentially even conflicting results. This is because there is often substantial flexibility in researchers’ analytical choices, an issue also referred to as “researcher degrees of freedom”. Combined with selective reporting of the smallest p-value or largest effect, researcher degrees of freedom may lead to an increased rate of false positive and overoptimistic results. In this paper, we address this issue by formalizing the multiplicity of analysis strategies as a multiple testing problem. As the test statistics of different analysis strategies are usually highly dependent, a naive approach such as the Bonferroni correction is inappropriate because it leads to an unacceptable loss of power. Instead, we propose using the “minP” adjustment method, which takes potential test dependencies into account and approximates the underlying null distribution of the minimal p-value through a permutation-based procedure. This procedure is known to achieve more power than simpler approaches while ensuring a weak control of the family-wise error rate. We illustrate our approach for addressing researcher degrees of freedom by applying it to a study on the impact of perioperative $$paO_2$$ p a O 2 on post-operative complications after neurosurgery. A total of 48 analysis strategies are considered and adjusted using the minP procedure. This approach allows to selectively report the result of the analysis strategy yielding the most convincing evidence, while controlling the type 1 error—and thus the risk of publishing false positive results that may not be replicable.

OBJECTIVES:. Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN:. Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING:. Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS:. In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS:. In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS:. HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Many-analysts studies explore how well an empirical claim withstands plausible alternative analyses of the same dataset by multiple, independent analysis teams. Conclusions from these studies typically rely on a single outcome metric (e.g. effect size) provided by each analysis team. Although informative about the range of plausible effects in a dataset, a single effect size from each team does not provide a complete, nuanced understanding of how analysis choices are related to the outcome. We used the Delphi consensus technique with input from 37 experts to develop an 18-item subjective evidence evaluation survey (SEES) to evaluate how each analysis team views the methodological appropriateness of the research design and the strength of evidence for the hypothesis. We illustrate the usefulness of the SEES in providing richer evidence assessment with pilot data from a previous many-analysts study.

Background: MRI (magnetic resonance imaging) represents the diagnostic image modality of choice in several conditions. With an increasing number of patients requiring MRI for diagnostic purposes, the issue of safety in patients with cardiac implantable electronic devices (CIED) undergoing this imaging modality will play an ever more important role. The purpose of this study was to assess the safety and device function following MRI in an unrestricted real-world cohort of patients with a wide array of cardiac devices. Methods: We conducted a retrospective single-center study including 1010 MRI studies conducted in adult patients (≥18 years) with an implanted CIED treated in the University Hospital of Munich (LMU) between July 2012 and March 2024. Patients with non-MR conditionally labeled leads, abandoned or epicardial leads, as well as lead fragments, were included for analysis. Results: Across a total of 1010 MRIs (920 total MR-conditional device generators) performed in patients with an implanted CIED, there were no deaths, reports of discomfort, palpitations, heating, or ventricular arrythmias in the 24 h following MRI. Only 2/1010 MRIs were followed by a reported atrial arrhythmia within 24 h, both in patients with an MR-conditional pacemaker (PM) device without an abandoned lead. No significant changes in device function following MRI from baseline were observed across all included CIEDs. Lastly, no instances of severe malfunction, such as generator failure, loss of capture, electrical reset, or inappropriate inhibition of pacing, were found in post-MRI interrogation reports across all MRI studies. Conclusions: Based on the analysis of 1010 MRIs undergone by patients with CIEDs, following standardized device interrogation, manufacturer-advised device programming, monitoring of vital function, and manufacturer-advised reprogramming, MRI can be performed safely and without adverse events or changes in device function.

Abstract Non-Pharmaceutical Interventions (NPIs) are community mitigation strategies, aimed at reducing the spread of illnesses like the coronavirus pandemic, without relying on pharmaceutical drug treatments. This study aims to evaluate the effectiveness of different NPIs across sixteen states of Germany, for a time period of 21 months of the pandemic. We used a Bayesian hierarchical approach that combines different sub-models and merges information from complementary sources, to estimate the true and unknown number of infections. In this framework, we used data on reported cases, hospitalizations, intensive care unit occupancy, and deaths to estimate the effect of NPIs. The list of NPIs includes: “contact restriction (up to 5 people)”, “strict contact restriction”, “curfew”, “events permitted up to 100 people”, “mask requirement in shopping malls”, “restaurant closure”, “restaurants permitted only with test”, “school closure” and “general behavioral changes”. We found a considerable reduction in the instantaneous reproduction number by “general behavioral changes”, “strict contact restriction”, “restaurants permitted only with test”, “contact restriction (up to 5 people)”, “restaurant closure” and “curfew”. No association with school closures could be found. This study suggests that some public health measures, including general behavioral changes, strict contact restrictions, and restaurants permitted only with tests are associated with containing the Covid-19 pandemic. Future research is needed to better understand the effectiveness of NPIs in the context of Covid-19 vaccination.

Throughout their education and when reading the scientific literature, students may get the impression that there is a unique and correct analysis strategy for every data analysis task and that this analysis strategy will always yield a significant and noteworthy result. This expectation conflicts with a growing realization that there is a multiplicity of possible analysis strategies in empirical research, which will lead to overoptimism and nonreplicable research findings if it is combined with result-dependent selective reporting. Here, we argue that students are often ill-equipped for real-world data analysis tasks and unprepared for the dangers of selectively reporting the most promising results. We present a seminar course intended for advanced undergraduates and beginning graduate students of data analysis fields such as statistics, data science, or bioinformatics that aims to increase the awareness of uncertain choices in the analysis of empirical data and present ways to deal with these choices through theoretical modules and practical hands-on sessions.

Abstract The Overall Anxiety Severity and Impairment Scale (OASIS) is a 5-item self-report measure that captures symptoms of anxiety and associated functional impairments. This study evaluates a German version (OASIS-D) that was administered to a convenience sample of 1398 primary care patients of whom 419 were diagnosed with panic disorder with/without agoraphobia. Psychometric properties were analyzed using classical test theory as well as probabilistic test theory. Factor analyses suggested a unitary (latent) factor structure. The internal consistency was good to excellent. Convergent as well as discriminant validity with other self-report measures was found. A sum score (range 0–20) of ≥ 8 emerged as optimal cut-score for screening purposes. A difference score of ≥ 5 was indicative of reliable individual change. A Rasch analysis of local item independence suggested response dependency between the first two items. Rasch analyses of measurement invariance detected noninvariant subgroups associated with age and gender. Analyses of validity and optimal cut-off score were solely based on self-report measures, which may have introduced method effects. In sum, the findings support the transcultural validity of the OASIS and indicate its applicability to naturalistic primary care settings. Caution is warranted when using the scale to compare groups that differ in age or gender.

BackgroundAlcohol use disorder (AUD) has become a major global health problem. Therapy for this condition is still a great challenge. Recently, it has become increasingly evident that computer-based training is a valuable addition to the treatment of addictive disorders. ObjectiveThis study aims to evaluate the web-based serious game SALIENCE (Stop Alcohol in Everyday Life-New Choices and Evaluations) as an add-on therapy for AUD. It combines the cue-exposure therapy approach with elements of decision-making training, enhanced by interactive panoramic images. The effects of SALIENCE training on levels of craving, attention, and cognitive bias are investigated. MethodsIn a randomized controlled trial, 62 participants with AUD undergoing 3 weeks of an extended alcohol detoxification program were randomly allocated to an intervention and a control group. A total of 49 individuals (mean age 44.04 y; 17/49, 35% female) completed all sessions and were included in the analysis. Only pretreatment data were available from the other 13 patients. Participants answered questionnaires related to alcohol consumption and craving and completed neuropsychological tasks at the beginning of the study and 2 weeks later to evaluate levels of attention and cognitive biases. During the 2-week period, 27 of the participants additionally performed the SALIENCE training for 30 minutes 3 times a week, for a total of 6 sessions. ResultsWe observed a significant decrease in craving in both groups: the control group (mean 15.59, SD 8.02 on the first examination day vs mean 13.18, SD 8.38 on the second examination day) and the intervention group (mean 15.19, SD 6.71 on the first examination day vs mean 13.30, SD 8.47 on the second examination day; F1,47=4.31; P=.04), whereas the interaction effect was not statistically significant (F1,47=0.06; P=.80). Results of the multiple linear regression controlling for individual differences between participants indicated a significantly greater decrease in craving (β=4.12; t36=2.34; P=.03) with the SALIENCE intervention. Participants with lower drinking in negative situations reduced their craving (β=.38; t36=3.01; P=.005) more than people with higher drinking in negative situations. ConclusionsThe general effectiveness of SALIENCE training as an add-on therapy in reducing alcohol craving was not confirmed. Nevertheless, taking into account individual differences (gender, duration of dependence, stress, anxiety, and drinking behavior in different situations), it was shown that SALIENCE training resulted in a larger reduction in craving than without. Notably, individuals who rarely consume alcohol due to negative affect profited the most from SALIENCE training. In addition to the beneficial effect of SALIENCE training, these findings highlight the relevance of individualized therapy for AUD, adapted to personal circumstances such as drinking motivation. Trial RegistrationClinicalTrials.gov NCT03765476; https://clinicaltrials.gov/show/NCT03765476

Summary: The complex cytoarchitecture of neurons poses significant challenges for the maturation of synaptic membrane proteins. It is currently unclear whether locally secreted synaptic proteins bypass the Golgi or whether they traffic through Golgi satellites (GSs). Here, we create a transgenic GS reporter mouse line and show that GSs are widely distributed along dendrites and are capable of mature glycosylation, in particular sialylation. We find that polysialylation of locally secreted NCAM takes place at GSs. Accordingly, in mice lacking a component of trans-Golgi network-to-plasma membrane trafficking, we find fewer GSs and significantly reduced PSA-NCAM levels in distal dendrites of CA1 neurons that receive input from the temporoammonic pathway. Induction of long-term potentiation at those, but not more proximal, synapses is severely impaired. We conclude that GSs serve the need for local mature glycosylation of synaptic membrane proteins in distal dendrites and thereby contribute to rapid changes in synaptic strength.

Abstract Background Multiple studies indicate that a lower plasma level of the acetylated form of the appetite-regulating hormone ghrelin and higher plasma levels of insulin lead to a reduction in subjective alcohol craving and a reduced mesolimbic cue reactivity in functional magnetic resonance imaging (fMRI) when being exposed to alcohol-associated stimuli. The ghrelin level can physiologically be reduced by the induction of stomach distension and the ingestion of glucose or lipids. Methods A total of 108 alcohol-dependent patients aged between 18 and 65 years are examined in the randomized, double-blind, placebo-controlled crossover study. After collecting demographic and psychometric data, participants take part in an alcohol exposure session. Afterwards, the participants go through the intervention condition (oral glucose intake) and the control condition (placebo intake) in a randomized order on two examination days. Blood samples are taken repeatedly (every 10 min) during the study course on both measuring days to determine changes in acetylated and total ghrelin and insulin plasma levels. In parallel, subjective alcohol craving after the glucose or placebo intake as the primary outcome is assessed using the Alcohol Urge Questionnaire (AUQ) and a visual analog scale (VAS). To examine the mesolimbic cue reactivity as the secondary outcome, a fMRI measurement is conducted while being exposed to alcohol-related stimuli. Appropriate statistical analysis will be used for the evaluation of the outcomes. Discussion If successful, the results of this study could offer alcohol-dependent patients a new potential option for acute short-term reduction of alcohol craving and thus prevent relapses and prolong periods of abstinence in the long term. Trial registration German Clinical Trials Register DRKS00022419 (UTN: U1111-1278-9428). Retrospectively registered on September 15, 2020.

Light affects humans beyond only image formation. Several studies have reported that light can increase daytime alertness and can therefore be positively utilized to counter daytime fatigue and increase productivity in workspaces. This systematic review summarized and analysed relevant literature that investigated the daytime alerting effect of light. Using keywords “alertness” and “light” in the title we retrieved a total of 142 studies via three search engines. Out of 142 studies, only 26 investigated the alerting effect of light during daytime. Six studies were excluded from the review based on the exclusion criteria. We reviewed twenty articles from the year 1991 until 2022 that have investigated the alerting effect of polychromatic and monochromatic light sources. Only seven out of twenty studies found an alerting effect that was recorded through positive self-assessment or enhancement of cognitive processes. The studies in which the lighting application would be transferrable for office use were highlighted. A specific common trend regarding the enhancement of alertness was not detected, as different lighting conditions and protocols were applied in the reviewed studies. More studies that investigate the effect of polychromatic light with intensities and spectral compositions that are suitable for application in realistic working environments are necessary to determine whether the daytime alerting effect of light will be significant.

Pathologic oligomerization of hyper-phosphorylated Tau is a hallmark of tauopathies. Here the authors show that the loss of tubulin a4 polyglutamylation reverses tau hyperphosphorylation, oligomerization and microglia activation in a tauopathy mouse.

Abstract Integration is often considered the core challenge and the defining characteristic of inter- and trans-disciplinary (ITD) research. Given its importance, it is surprising that the current system of higher education does not provide permanent positions for integration experts; i.e., experts who lead, administer, manage, monitor, assess, accompany, and/or advise others on integration within ITD projects or programs. Based on empirical results of an ITD 2019 Conference Workshop entitled “Is there a new profession of integration experts on the rise?” held in Gothenburg, Sweden, and our own experience in leading and studying ITD integration, the present article sheds light on the overarching question, “What are integration experts?”, thus contributing to the emerging literature on integration and integration expertise. We use direct quotes from participants to substantiate workshop results and triangulate them with recent literature on ITD research as well as Science of Team Science (SciTS) and Science and Technology Studies (STS). We conclude our article by discussing possible unintended consequences of establishing academic careers for integration experts, and suggest four complementary ways to support them, while mitigating potentially negative consequences: (a) establishing an international Community of Practice (CoP) to foster peer-to-peer exchange among integration experts, create greater visibility, and develop ideas for transforming academic structures; (b) studying academic careers of integration experts to provide empirical evidence of “successful” examples and disclose different ways of establishing related academic positions; (c) funding respective positions and aligning metrics for ITD research to foster integration within ITD projects or programs; and (d) engaging in collaborative dialog with academic institutions and funding agencies to present empirical results and lessons learnt from (a) and (b) to support them in establishing and legitimating careers for integration experts. If academia is to be serious about addressing the most pressing environmental and societal problems of our time, it needs to integrate its integrators.

RationaleAttention deficit/hyperactivity disorder (ADHD) is common in alcohol use disorder (AUD). Continuous performance tests (CPTs) allow to measure ADHD related deficits in a laboratory setting. Most studies on this topic focused on CPTs measuring inattention or impulsivity, disregarding hyperactivity as one of the core symptoms of ADHD.MethodsWe examined N = 47 in three groups (ADHD N = 19; AUD N = 16; ADHD + AUD N = 12) with questionnaires on ADHD core symptoms, executive functioning (EF), mind wandering, and quality of life (QoL). N = 46 (ADHD N = 16; AUD N = 16; ADHD + AUD N = 14) were examined with a CPT (QbTest®) that also measures motor activity objectively.ResultsInattention and impulsivity were significantly increased in AUD vs. ADHD and in AUD vs. ADHD + AUD. Hyperactivity was significantly higher in ADHD + AUD vs. ADHD and ADHD + AUD vs. AUD, but not in ADHD vs. AUD. EF was lower in both ADHD groups vs. AUD. Mind wandering was increased in both ADHD groups vs. AUD. QoL was significantly lower in ADHD + AUD compared to AUD. In contrast, results of the QbTest were not significantly different between groups.ConclusionQuestionnaires are more useful in assessing ADHD core symptoms than the QbTest®. Hyperactivity appears to be a relevant symptom in ADHD + AUD, suggesting a possible pathway from ADHD to AUD. The lower QoL in ADHD + AUD emphasizes the need for routine screening, diagnostic procedures and treatment strategies for this patient group.

Dynamic façades play an important role in enhancing the overall performance of buildings: they respond to the environmental conditions and adjust the amount of transmitted solar radiation. This paper proposes a simulation-based framework to evaluate the energy and comfort performance of different control strategies for switchable electrochromic glazing (EC). The presented method shows the impact of a model predictive control (MPC) on energy savings and on visual and thermal comfort for different orientations compared to other strategies. Besides manual operation and conventional rule-based controls, the benchmark in this study was a simulation-based control (multi-objective penalty-based control) with optimal performance. The hourly results of various control cases were analyzed based on the established performance indicators and criteria. The cumulative annual results show the capabilities and limitations of each control strategy for an EC glazing. For a temperate climate (Mannheim, Germany), results showed that an MPC for EC glazing provides visual and thermal comfort while saving energy of up to 14%, 37%, 37%, and 34% respectively for facing north, east, south, and west relative to the base-case.

BackgroundMales consume more alcohol than females, and alcohol use disorder (AUD) is more prevalent in males than females. However, females progress faster to AUD. Sex differences in neural alcohol cue reactivity were previously observed in young social drinkers, indicating a role of hypersensitivity to alcohol-related cues in very early stages of addiction. To our knowledge, this is the first study on patients diagnosed with AUD to test sex differences in neural reactivity to alcohol cues in order to widen previous findings.MethodsWe analyzed data from previous studies, using a well-established functional magnetic resonance imaging (fMRI) paradigm to compare neural reactivity to alcohol cues between 42 female and 124 male patients with AUD (mean age 45 and 46 years) in predefined regions of interest that were implicated by previous studies (ventral and dorsal striatum as well as caudate, putamen, amygdala, hippocampus, insula, anterior cingulate cortex, and medial prefrontal cortex) using independent samples t-tests. Post-hoc, effect size calculations were performed.ResultsThroughout all nine regions of interest, we found no statistically significant sex differences in neural reactivity toward alcoholic pictures alone or in comparison to neutral pictures (p > 0.05, FDR-corrected). Post-hoc effect size estimates indicated a magnitude between 0.137 and 0.418 (Hedge’s g) on alcohol reactivity to alcohol cues compared to neutral cues and indicate very small to less than medium effect sizes in the direction of higher cue reactivity in female patients.ConclusionPrevious studies showed sex differences in neural alcohol cue reactivity in younger social and problematic alcohol drinkers, i.e., stronger striatal cue-reactivity in males. After correction for multiple comparisons, we did not observe significant sex differences in a cohort of middle-aged females and males with AUD. Sex differences that are present during early phases of addiction development might disappear at later stages of AUD and might thus be considered as clinically less relevant in patients with more severe AUD.

Abstract Background Percutaneous dilatational tracheotomy (PDT) has become an established procedure in intensive care units (ICU). However, the safety of this method has been under debate given the growing number of critically ill patients with high bleeding risk receiving anticoagulation, dual antiplatelet therapy (DAPT) or even a combination of both, i.e. triple therapy. Therefore, the purpose of this study, including such a high proportion of patients on antithrombotic therapy, was to investigate whether PDT in high-risk ICU patients is associated with elevated procedural complications and to analyse the risk factors for bleeding occurring during and after PDT. Methods PDT interventions conducted in ICUs at 12 European sites between January 2016 and October 2019 were retrospectively analysed for procedural complications. For subgroup analyses, patient stratification into clinically relevant risk groups based on anticoagulation and antiplatelet treatment regimens was performed and the predictors of bleeding occurrence were analysed. Results In total, 671 patients receiving PDT were included and stratified into four clinically relevant antithrombotic treatment groups: (1) intravenous unfractionated heparin (iUFH, prophylactic dosage) (n = 101); (2) iUFH (therapeutic dosage) (n = 131); (3) antiplatelet therapy (aspirin and/or P2Y12 receptor inhibitor) with iUFH (prophylactic or therapeutic dosage) except for triple therapy (n = 290) and (4) triple therapy (DAPT with iUFH in therapeutic dosage) (n = 149). Within the whole cohort, 74 (11%) bleedings were reported to be procedure-related. Bleeding occurrence during and after PDT was independently associated with low platelet count (OR 0.73, 95% CI [0.56, 0.92], p = 0.009), chronic kidney disease (OR 1.75, 95% CI [1.01, 3.03], p = 0.047) and previous stroke (OR 2.13, 95% CI [1.1, 3.97], p = 0.02). Conclusion In this international, multicenter study bronchoscopy-guided PDT was a safe and low-complication airway management option, even in a cohort of high risk for bleeding on cardiovascular ICUs. Low platelet count, chronic kidney disease and previous stroke were identified as independent risk factors of bleeding during and after PDT but not triple therapy.

The main aim of this paper is a multi-objective evaluation of electrochromic (EC) glazing with consideration of operational and embodied energy including the impact of switchable glazing on visual and thermal comfort. Different criteria were evaluated for the refurbishment of a prototypical 30 m2 office room in Mannheim, Germany. The room prototype was assumed as lightweight and heavyweight construction, where refurbishment strategies such as the addition of thermal insulation and the exchange of windows were investigated. For the window exchange, EC-glazing was compared to a high-performance glazing with solar coating. The EC-glazing was automated via a rule-based (incident radiation) and a penalty-based (multi-objective prediction) control strategy. Regarding operational energy, the EC-glazing performed slightly better than the glazing with solar coating. However, the results showed that the high amount of embodied energy in EC-glazings could not be justified by the rather small savings of the operational energy. On the other hand, with the penalty-based control, the EC-glazing improved visual comfort significantly in comparison to the static glazing with solar coating. The decision to replace the original glazing with an EC-glazing as opposed to a glazing with solar coating would have to be based on the improvement of occupants’ comfort, due to an unjustifiable increase of embodied energy and marginal savings of operational energy.

Abstract In 2007 the German government passed smoke-free legislation, leaving the details of implementation to the individual federal states. In January 2008 Bavaria implemented one of the strictest laws in Germany. We investigated its impact on pregnancy outcomes and applied an interrupted time series (ITS) study design to assess any changes in preterm birth, small for gestational age (primary outcomes), and low birth weight, stillbirth and very preterm birth. We included 1,236,992 singleton births, comprising 83,691 preterm births and 112,143 small for gestational age newborns. For most outcomes we observed unclear effects. For very preterm births, we found an immediate drop of 10.4% (95%CI − 15.8, − 4.6%; p = 0.0006) and a gradual decrease of 0.5% (95%CI − 0.7, − 0.2%, p = 0.0010) after implementation of the legislation. The majority of subgroup and sensitivity analyses confirm these results. Although we found no statistically significant effect of the Bavarian smoke-free legislation on most pregnancy outcomes, a substantial decrease in very preterm births was observed. We cannot rule out that despite our rigorous methods and robustness checks, design-inherent limitations of the ITS study as well as country-specific factors, such as the ambivalent German policy context have influenced our estimation of the effects of the legislation.

Abstract Background Colorectal cancer (CRC) is the second most common malignant disease and the second most common cause of cancer death in Germany. Official CRC screening starts at age 50. As there is evidence that individuals with a family history of CRC have an increased risk of developing CRC before age 50, there are recommendations to start screening for this group earlier. This study aims to evaluate the clinical and economic effects of a risk-adapted screening program for CRC in individuals between 25 and 50 years of age with potentially increased familial CRC risk. Methods FARKOR (Familiäres Risiko für das Kolorektale Karzinom) is a population-based prospective intervention study. All members of cooperating statutory health insurance companies between 25 and 50 years of age living in a model region in Germany (federal state of Bavaria, 3.5 million inhabitants in this age group) can participate in the program between October 2018 and March 2020. Recruitment takes place through physicians and through a public campaign. Additionally, insurances contact recently diagnosed CRC patients in order to encourage their relatives to participate in the program. Physicians assess a participant’s familial history of CRC using a short questionnaire. All participants with a family history of CRC are invited to a shared decision making process to decide on further screening options consisting of either undergoing an immunological test for fecal occult blood or colonoscopy. Comprehensive data collection based on self-reported lifestyle information, medical documentation and health administrative databases accompanies the screening program. Longterm benefits, harms and the cost-effectiveness of the risk-adapted CRC screening program will be assessed by decision analytic modeling. Discussion The data collected in this study will add important pieces of information that are still missing in the evaluation of the effects and the cost-effectiveness of a risk-adapted CRC screening strategy for individuals under 50 years of age. Trial registration German Clinical Trials Register, DRKS-IDDRKS00015097 .

RationaleChildhood maltreatment (CM) leads to detrimental mental health outcomes, such as substance use disorders (SUD). This study examined prevalence and severity of all five types of CM with respect to specific substances and sex in treatment-seeking individuals with SUD. The influences of type of CM and symptoms of depressiveness, anxiety, and perceived stress on substance craving at admission as well as craving reduction during SUD treatment were examined.MethodsN = 546 patients in treatment for SUD and N = 109 individuals in opioid maintenance treatment filled out questionnaires regarding CM (Childhood Trauma Questionnaire) and psychopathologies. Substance craving was assessed throughout treatment using the Mannheim Craving Scale. Group differences in CM, type of substance and sex were examined. General linear models were applied to examine influences on substance craving.ResultsHigher prevalence and severity of all five subtypes of CM were observed in individuals with SUD compared to the general population. Women were more severely affected by emotional and sexual abuse than men. Patients with cannabis use disorder reported more severe experiences of emotional abuse compared to all other substances. Craving at admission to treatment was influenced by emotional abuse, however, symptoms of depressiveness, anxiety, and perceived stress contributed to craving at admission or craving reduction during treatment.ConclusionCM relates to SUD and should be incorporated in prevention and treatment of SUD. Underlying mechanisms of the association might relate to impairments in processing and regulation of stress, emotions, and interpersonal relations following a history of CM.

Any large dataset can be analyzed in a number of ways, and it is possible that the use of different analysis strategies will lead to different results and conclusions. One way to assess whether the results obtained depend on the analysis strategy chosen is to employ multiple analysts and leave each of them free to follow their own approach. Here, we present consensus-based guidance for conducting and reporting such multi-analyst studies, and we discuss how broader adoption of the multi-analyst approach has the potential to strengthen the robustness of results and conclusions obtained from analyses of datasets in basic and applied research.

For a given research question, there are usually a large variety of possible analysis strategies acceptable according to the scientific standards of the field, and there are concerns that this multiplicity of analysis strategies plays an important role in the non-replicability of research findings. Here, we define a general framework on common sources of uncertainty arising in computational analyses that lead to this multiplicity, and apply this framework within an overview of approaches proposed across disciplines to address the issue. Armed with this framework, and a set of recommendations derived therefrom, researchers will be able to recognize strategies applicable to their field and use them to generate findings more likely to be replicated in future studies, ultimately improving the credibility of the scientific process.

Longwave radiative heat transfer is a key determinant of energy consumption in buildings and view factor calculations are therefore required for the detailed simulation of heat transfer between buildings and their environment as well as for heat exchange within rooms. Typically, these calculations are either derived through analytical means or performed as a part of the simulation process. This paper describes the methodology for employing RADIANCE, a command-line open-source raytracing software, for performing view factor calculations. Since it was introduced in the late-1980s, RADIANCE has been almost exclusively employed as the back-end engine for lighting simulations. We discuss the theoretical basis for calculating view factors through Monte Carlo calculations with RADIANCE and propose a corresponding workflow. The results generated through RADIANCE are validated by comparing them with analytical solutions. The fundamental methodology proposed in this paper can be scaled up to calculate view factors for more complex, practical scenarios. Furthermore, the portability, multi-processing functionality and cross-platform compatibility offered by RADIANCE can also be employed in the calculation of view factors.

Thermal comfort is one of the most important factors for occupant satisfaction and, as a result, for the building energy performance. Decentralized heating and cooling systems, also known as “Personal Environmental Comfort Systems” (PECS), have attracted significant interest in research and industry in recent years. While building simulation software is used in practice to improve the energy performance of buildings, most building simulation applications use the PMV approach for comfort calculations. This article presents a newly developed building controller that uses a holistic approach in the consideration of PECS within the framework of the building simulation software Esp-r. With PhySCo, a dynamic physiology, sensation, and comfort model, the presented building controller can adjust the setpoint temperatures of the central HVAC system as well as control the use of PECS based on the thermal sensation and comfort values of a virtual human. An adaptive building controller with a wide dead-band and adaptive setpoints between 18 to 26 °C (30 °C) was compared to a basic controller with a fixed and narrow setpoint range between 21 to 24 °C. The simulations were conducted for temperate western European climate (Mannheim, Germany), classified as Cfb climate according to Köppen-Geiger. With the adaptive controller, a 12.5% reduction in end-use energy was achieved in winter. For summer conditions, a variation between the adaptive controller, an office chair with a cooling function, and a fan increased the upper setpoint temperature to 30 °C while still maintaining comfortable conditions and reducing the end-use energy by 15.3%. In spring, the same variation led to a 9.3% reduction in the final energy. The combinations of other systems were studied with the newly presented controller.

Abstract Background Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. Methods We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene. Results Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). Conclusions Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients.

Daylight is important for the well-being of humans. Therefore, many office buildings use large windows and glass facades to let more daylight into office spaces. However, this increases the chance of glare in office spaces, which results in visual discomfort. Shading systems in buildings can prevent glare but are not effectively adapted to changing sky conditions and sun position, thus losing valuable daylight. Moreover, many shading systems are also aesthetically unappealing. Electrochromic (EC) glass in this regard might be a better alternative, due to its light transmission properties that can be altered when a voltage is applied. EC glass facilitates zoning and also supports control of each zone separately. This allows the right amount of daylight at any time of the day. However, an effective control strategy is still required to efficiently control EC glass. Reinforcement learning (RL) is a promising control strategy that can learn from rewards and penalties and use this feedback to adapt to user inputs. We trained a Deep Q learning (DQN) agent on a set of weather data and visual comfort data, where the agent tries to adapt to the occupant’s feedback while observing the sun position and radiation at given intervals. The trained DQN agent can avoid bright daylight and glare scenarios in 97% of the cases and increases the amount of useful daylight up to 90%, thus significantly reducing the need for artificial lighting.

Solar radiation data is essential for the development of many solar energy applications ranging from thermal collectors to building simulation tools, but its availability is limited, especially the diffuse radiation component. There are several studies aimed at predicting this value, but very few studies cover the generalizability of such models on varying climates. Our study investigates how well these models generalize and also show how to enhance their generalizability on different climates. Since machine learning approaches are known to generalize well, we apply them to truly understand how well they perform on different climates than they are originally trained. Therefore, we trained them on datasets from the U.S. and tested on several European climates. The machine learning model that is developed for U.S. climates not only showed low mean absolute error (MAE) of 23 W/m2, but also generalized very well on European climates with MAE in the range of 20 to 27 W/m2. Further investigation into the factors influencing the generalizability revealed that careful selection of the training data can improve the results significantly.

As rapid growth in the construction industry continues to occur in China, the increased demand for a higher standard living is driving significant growth in energy use and demand across the country. Building codes and standards have been implemented to head off this trend, tightening prescriptive requirements for fenestration component measures using methods similar to the U.S. model energy code American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) 90.1. The objective of this study is to (a) provide an overview of applicable code requirements and current efforts within China to enable characterization and comparison of window and shading products, and (b) quantify the load reduction and energy savings potential of several key advanced window and shading systems, given the divergent views on how space conditioning requirements will be met in the future. System-level heating and cooling loads and energy use performance were evaluated for a code-compliant large office building using the EnergyPlus building energy simulation program. Commercially-available, highly-insulating, low-emittance windows were found to produce 24%–66% lower perimeter zone HVAC electricity use compared to the mandated energy-efficiency standard in force (GB 50189-2005) in cold climates like Beijing. Low-e windows with operable exterior shading produced up to 30%–80% reductions in perimeter zone HVAC electricity use in Beijing and 18%–38% reductions in Shanghai compared to the standard. The economic context of China is unique since the cost of labor and materials for the building industry is so low. Broad deployment of these commercially available technologies with the proper supporting infrastructure for design, specification, and verification in the field would enable significant reductions in energy use and greenhouse gas emissions in the near term.

Exposure measurement error represents one of the most important sources of uncertainty in epidemiology. When exposure uncertainty is not or only poorly accounted for, it can lead to biased risk estimates and a distortion of the shape of the exposure-response relationship. In occupational cohort studies, the time-dependent nature of exposure and changes in the method of exposure assessment may create complex error structures. When a method of group-level exposure assessment is used, individual worker practices and the imprecision of the instrument used to measure the average exposure for a group of workers may give rise to errors that are shared between workers, within workers or both. In contrast to unshared measurement error, the effects of shared errors remain largely unknown. Moreover, exposure uncertainty and magnitude of exposure are typically highest for the earliest years of exposure. We conduct a simulation study based on exposure data of the French cohort of uranium miners to compare the effects of shared and unshared exposure uncertainty on risk estimation and on the shape of the exposure-response curve in proportional hazards models. Our results indicate that uncertainty components shared within workers cause more bias in risk estimation and a more severe attenuation of the exposure-response relationship than unshared exposure uncertainty or exposure uncertainty shared between individuals. These findings underline the importance of careful characterisation and modeling of exposure uncertainty in observational studies.

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10−4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%−60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.

Research and policy processes in many fields, such as sustainability and health, are increasingly relying on transdisciplinary cooperation among a multitude of governmental, nongovernmental, and private actors from local to global levels. In the absence of hierarchical chains of command, multistakeholder governance may accommodate conflicting or diverse interests and facilitate collective action, but its effectiveness depends on its capacity to integrate systems, transformation, and target knowledge. Approaches to foster such governance are nascent and quickly evolving, and methodological standards to facilitate comparison and learning from best practice are needed. However, there is currently no evaluation approach that (i) comprehensively assesses the capacity for knowledge integration in multistakeholder governance, (ii) draws on the best available knowledge that is being developed in various fields, and (iii) combines a systematic and transferable methodological design with pragmatic feasibility. We brought together 20 experts from institutions in nine countries, all working on evaluation approaches for collaborative science-policy initiatives. In a synthesis process that included a 2-day workshop and follow-up work among a core group of participants, we developed a tool for evaluating knowledge integration capacity in multistakeholder governance (EVOLvINC). Its 23 indicators incorporate previously defined criteria and components of transdisciplinary evaluations into a single, comprehensive framework that operationalizes the capacity for integrating systems, target, and transformation knowledge during an initiative's (a) design and planning processes at the policy formulation stage, (b) organization and working processes at the implementation stage, and (c) sharing and learning processes at the evaluation stage of the policy cycle. EVOLvINC is (i) implemented through a questionnaire, (ii) builds on established indicators where possible, (iii) offers a consistent and transparent semiquantitative scoring and aggregation algorithm, and (iv) uses spider diagrams for visualizing results. The tool builds on experience and expertise from both the northern and southern hemispheres and was empirically validated with seven science-policy initiatives in six African and Asian countries. As a generalized framework, EVOLvINC thus enables a structured reflection on the capacity of multistakeholder governance processes to foster knowledge integration. Its emphasis on dialog and exploration allows adaptation to contextual specificities, highlights relative strengths and weaknesses, and suggests avenues for shaping multistakeholder governance toward mutual learning, capacity building, and strengthened networks. The validation suggests that the adaptive capacity of multistakeholder governance could be best enhanced by considering systems characteristics at the policy formulation stage and fostering adaptive and generic learning at the evaluation stage of the policy cycle.

What methods and procedures support transdisciplinary knowledge integration? We address this question by exploring knowledge integration within four thematic synthesis processes of the Swiss National Research Programme 61 Sustainable Water Management (NRP 61). Drawing on literature from inter- and transdisciplinary research, we developed an analytical framework to map different methods and procedures of knowledge integration. We use this framework to characterize the variety of methods and procedures that were combined in the four processes to produce thematic synthesis reports. We suggest that the variety of combinations observed reflects the different objectives and questions that guided the processes of knowledge integration as well as the different roles that leaders assumed in these processes. Although the framework was developed in the course of NRP 61, we consider it as a basis for designing ex ante new synthesis processes by defining and sequencing different synthesis stages and by identifying, for each stage, the contributions of specific scientific and societal actors, the purpose of their contributions, and the methods and procedures supporting their contributions. Used in a formative evaluation process, the framework supports reflection on and adaptation of synthesis processes and also facilitates the generation of new knowledge for designing future processes.

The article presents the first results of a qualitative research study on writing in a foreign language with the help of Google Translator. It examines the processes of the construction of verbal and discursive forms during group discussion on the translation of a tourist website structures ensuing from a tourist website const. This study took place in the 2013/2014 academic year, and it was based on a video recording of about 12 hours of group work by 16 students while planning and producing a draft of the German translation of the homepage of an Italian tourist site. This study highlights both the advantages and disadvantages of the use of an online translation resource by students with basic knowledge of a foreign language.