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Quantitative sensory testing (QST) is a standard procedure in medicine to describe sensory patterns in various pathologies. The aim of this prospective clinical study was to define reference values of the trigeminal nerve (V3), including taste qualities, to create a compatibility for sensory loss or gain in pathologies. Fifty-one patients were included, and a standardized testing battery with 11 QST parameters according to the German Research Network on Neuropathic Pain (DFNS) was applied complemented by quantitative gustatory assessments. Significant somatosensory differences were found between the test sites (MDT at the chin, WDT at the lower lip) but no effect was detected for gender, age, and between body types. Taste sensitivity was dependent on concentration, gender (females being more sensitive) and increasing age (for bitter and sour taste). We provide reference values for somatosensory and gustatory testing of the facial area. Our data facilitate the detection of neurosensory abnormalities in the orofacial region. This might also serve as a control setting for COVID-19.

Visual examinations are commonly used to analyze spinal posture. Even though they are simple and fast, their interrater reliability is poor. Suitable alternatives should be objective, non-invasive, valid and reliable. Videorasterstereography (VRS) is a corresponding method that is increasingly becoming established. However, there is a lack of reference data based on adequate numbers of participants and structured subgroup analyses according to sex and age. We used VRS to capture the spinal posture of 201 healthy participants (aged 18-70 years) divided into three age cohorts. Three-dimensional reference data are presented for the global spine parameters and for every vertebral body individually (C7-L4) (here called the specific spine parameters). The vertebral column was found to be systematically asymmetric in the transverse and the coronal planes. Graphical presentations of the vertebral body posture revealed systematic differences between the subgroups; however, large standard deviations meant that these differences were not significant. In contrast, several global parameters (e.g., thoracic kyphosis and lumbar lordosis) indicated differences between the analyzed subgroups. The findings confirm the importance of presenting reference data not only according to sex but also according to age in order to map physiological posture changes over the life span. The question also arises as to whether therapeutic approximations to an almost symmetrical spine are biomechanically desirable.

Background: Everybody has the right to decide whether to receive specific medical treatment or not and to provide their free, prior and informed consent to do so. As dementia progresses, people with Alzheimer's dementia (PwAD) can lose their capacity to provide informed consent to complex medical treatment. When the capacity to consent is lost, the autonomy of the affected person can only be guaranteed when an interpretable and valid advance directive exists. Advance directives are not yet common in Germany, and their validity is often questionable. Once the dementia diagnosis has been made, it is assumed to be too late to write an advance directive. One approach used to support the completion of advance directives is 'Respecting Choices' ® -an internationally recognised, evidence-based model of Advance Care Planning (ACP), which, until now, has not been evaluated for the target group of PwAD. This study's aims include (a) to investigate the proportion of valid advance directives in a memory clinic population of persons with suspected AD, (b) to determine the predictors of valid advance directives, and (c) to examine whether the offer of ACP can increase the proportion of valid advance directives in PwAD., Method: We intend to recruit at least N = 250 participants from two memory clinics in 50 consecutive weeks. Of these, the first 25 weeks constitute the baseline phase (no offer of ACP), the following 25 weeks constitute the intervention phase (offer of ACP). The existence and validity of an advance directive will be assessed twice (before and after the memory clinic appointment). Moreover, potential predictors of valid advance directives are assessed., Discussion: The results of this study will enhance the development of consent procedures for advance directives of PwAD based on the ACP/Respecting Choices (R) approach. Therefore, this project contributes towards increasing the autonomy and inclusion of PwAD and the widespread acceptance of valid advance directives in PwAD. Trial Registration DRKS, DRKS00026691, registered 15th of October 2021, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00026691., (© 2022. The Author(s).)

To compare four plaque indices used in orthodontics. An objective, quantitative plaque index and three subjective conventional plaque indices were analyzed. The study included n = 50 photographs of n = 50 subjects with a multibracket appliance (MB) in the maxilla and mandible. Photographs were taken using Digital Plaque Imaging Analysis (DPIA) and the Percentage Plaque Index (PPI) was calculated. The conventional plaque indices, a modified version of the Turesky-modification of the Quigley & Hein Index (TQH index), Attin index, and modified bonded bracket index (mBB index) were collected from n = 14 evaluators using the DPIA photographs. The evaluators had different levels of orthodontic experience: n = 4 evaluators had little orthodontic experience, n = 5 evaluators had moderate orthodontic experience, and n = 5 evaluators had a lot of orthodontic experience. Plaque accumulation was assessed differently with the plaque indices. Thus, the plaque indices are not interchangeable. We recommend DPIA as an objective, quantitative and sensitive method for plaque determination in scientific studies. The simple statistical evaluation offers a great advantage over conventional plaque indices., (© 2022. The Author(s).)

Objective: The current study was undertaken to prospectively explore whether having low levels of von Willebrand factor (vWF) antigen and vWF activity reduce the risk for cardiovascular disease and death., Methods: VWF antigen and vWF activity were measured by enzyme-linked immunosorbent assay and an immunological-based assay, respectively, in a subsample of 4857 individuals aged between 35 and 74 years old, enrolled between April 2007 and October 2008 in the population-based Gutenberg Health Study. VWF antigen and activity below the 20th percentile was set as a measure of "low vWF." Adjusted robust Poisson regression models were used to analyze the relation between low vWF and the incidence of cardiovascular disease (CVD). Consequent adjusted cox regression models as well as cumulative incidence plots were calculated to explore the relation between all-cause and cardiovascular mortality and low vWF., Results: VWF activity levels <20th percentile (i.e., <76.2%) were associated with a decreased relative risk for CVD (RR: 0.59, 95% CI: 0.37-0.95), despite adjusting for age and sex. After adjusting for levels of F-VIII, the association persisted (RR: 0.60, 95% CI: 0.36-0.99). The cumulative incidence plots demonstrated that vWF antigen <20th percentile significantly correlated with decreased cardiovascular mortality. VWF antigen<20th percentile (i.e., <83%) was significantly associated with lower risk of all-cause mortality, despite adjusting for clinical factors (RR: 61, 95% CI: 0.41-0.91)., Conclusion: The study demonstrated that having low vWF activity levels were associated with a lower risk for CVD. Additionally, it revealed a decreased risk of cardiovascular and all-cause mortality in individuals with low levels of vWF antigen, shining new light on vWF as a potential target for novel therapies., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: During the SARS-CoV-2 pandemic, preventive measures like physical distancing, wearing face masks, and hand hygiene have been widely applied to mitigate viral transmission. Beyond increasing vaccination coverage, preventive measures remain urgently needed. The aim of the present project was to assess the effect of protective behavior on SARS-CoV-2 infection risk in the population., Methods: Data of the Gutenberg COVID-19 Study (GCS), a prospective cohort study with a representative population-based sample, were analyzed. SARS-CoV-2 infections were identified by sequential sampling of biomaterial, which was analyzed by RT-qPCR and two antibody immunoassays. Self-reported COVID-19 test results were additionally considered. Information on protective behavior including physical distancing, wearing face masks, and hand hygiene was collected via serial questionnaire-based assessments. To estimate adjusted prevalence ratios and hazard ratios, robust Poisson regression and Cox regression were applied., Results: In total, 10,250 participants were enrolled (median age 56.9 [43.3/68.6] years, 50.8% females). Adherence to preventive measures was moderate for physical distancing (48.3%), while the use of face masks (91.5%) and the frequency of handwashing (75.0%) were high. Physical distancing appeared to be a protective factor with respect to SARS-CoV-2 infection risk independent of sociodemographic characteristics and individual pandemic-related behavior (prevalence ratio [PR] = 0.77, 95% confidence interval [CI] 0.62-0.96). A protective association between wearing face masks and SARS-CoV-2 transmission was identified (PR = 0.73, 95% CI 0.55-0.96). However, the protective effect declined after controlling for potential confounding factors (PR = 0.96, 95% CI 0.68-1.36). For handwashing, this investigation did not find a beneficial impact. The adherence to protective behavior was not affected by previous SARS-CoV-2 infection or immunization against COVID-19., Conclusion: The present study suggests primarily a preventive impact of physical distancing of 1.5 m, but also of wearing face masks on SARS-CoV-2 infections, supporting their widespread implementation. The proper fit and use of face masks are crucial for effectively mitigating the spread of SARS-CoV-2 in the population., (© 2022. The Author(s).)

Background: Airway management in children is challenging due to anatomical and physiological differences. This randomized trial investigates whether anaesthesia residents can intubate the paediatric trachea more quickly and with a higher success rate using the King Vision™ Paediatric aBlade™ video laryngoscope (KVL) compared to conventional direct laryngoscopy (DL). Methods: Eleven anaesthesia residents (mean age: 31 years, mean training status 47 months) were each asked to perform intubations with the KVL and DL in paediatric patients. The primary outcome was the first-attempt success rate. Secondary outcomes were the time to best view (TTBV), time to placement of the tracheal tube (TTP), time to ventilation (TTV), and participant-reported ease of use on a Likert scale. Results: 105 intubations with the KVL and 106 DL were performed by the residents. The success rate on the first attempt with the KVL was 81%, and the success rate on the first attempt within a given time limit of 30 s was 45%, which was lower than with DL (93% and 77% with time limit, p < 0.01). The median TTBV [IQR] on the first attempt with KVL was 7 [5−10] s, the median TTP was 28 [19−44] s, and the median TTV was 51 [39−66] s. DL-mediated intubation was significantly faster (TTP: 17 [13−23] s; p < 0.0001 and TTV: 34 [28−44] s; p < 0.001). Application of the KVL was rated as difficult or very difficult by 60% of the residents (DL: 5%). Conclusion: In contrast to promising data on the paediatric training manikin, residents took longer to intubate the airway in children with the KVL and were less successful compared to the DL. Therefore, the KVL should not be recommended for learning paediatric intubation by residents.

Results: 18,335 eyes of 9,559 participants aged 40 to 80 years were included in the analysis. Median pupil diameter was 4.19 mm in right eyes and 4.12 mm in left eyes. A smaller pupil was associated with older age, hyperopic refractive error, previous cataract surgery, diabetes, obesity, and ACE inhibitor intake, whereas wider pupil was associated with female gender, arterial hypertension, intake of tricyclic antidepressants, and intake of SNRI and tetracyclic antidepressants. Socioeconomic status and smoking were not associated with pupil size., Conclusion: Individuals of older age, after cataract surgery, under therapy with ACE inhibitors and with diabetes have a smaller pupil. This should be taken into account when planning nonmydriatic fundus photography-based screening programs, for instance, for diabetic retinopathy., Competing Interests: The authors declare that they have no conflicts of interest. There are no patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the journal policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Beutel ME received speaker honorarium from Pfizer Deutschland GmbH., (Copyright © 2022 Marian Kiel et al.)

Objectives/hypothesis: Hearing loss is the most common sensory impairment worldwide. It restricts patients in many aspects of their daily lives and can lead to social exclusion. Understanding this burden is a mandatory requirement for the care of those affected. Therefore, the aim of this study was to estimate the burden of hearing loss in a large German cohort., Study Design: Cohort study., Methods: The Gutenberg Health Study is designed as a single-center, prospective, and observational cohort study and representative for the city of Mainz, Germany, with its district. Participants were interviewed concerning common otologic symptoms and tested by pure-tone audiometry. The primary outcome was hearing impairment stratified by age and sex. The prevalence of tinnitus was estimated for a subcohort to calculate disability-adjusted life years (DALYs). All results were weighted by the European Standard Population (ESP) 2013., Results: A total of 5,024 participants (mean age: 61.2 years, 2,591 men and 2,433 women) were included in the study. Hearing impairment showed the following prevalence: 28.2% (95% confidence interval [CI], 26.9%-29.4%) mild impairment, 10.1% (95% CI, 9.3%-11.0%) moderate impairment, 2.3% (95% CI, 1.9%-2.7%) moderately severe impairment, 0.2% (95% CI, 0.1%-0.4%) severe impairment, 0% (95% CI, 0.0%-0.1%) profound impairment, and 0.1% (95% CI, 0.0%-0.2%) complete impairment. Weighted for the ESP 2013 (all ages), hearing impairment across all levels (with/without tinnitus) causes a total of 2,118.97 DALYs per 100,000., Conclusion: With 40.9% affected, the hearing loss represents a relevant burden of the German population. Understanding this will provide the basis for future guidelines on how to care for these patients., Level of Evidence: 2 Laryngoscope, 132:1843-1849, 2022., (© 2021 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE)., Methods and Results: The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium., Conclusions: Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Changes in peripheral corneal thickness are described in various corneal diseases such as corneal ectasia. However, few data exist describing the increase in corneal thickness from central to peripheral and reporting the normal distribution of corneal thickness in rings around the corneal centre. The aim of this study was to report these cornea characteristics and investigate associated factors in a population-based setting., Methods: The Gutenberg Health Study is a prospective, population-based study examining participants in a 5-year follow-up (age range 40-80 years) using Scheimpflug imaging. Corneal thickness was assessed in each participant at the apex, as well as in the corneal centre (thinnest corneal thickness) and in rings with 2, 4, 6, 8 and 10 mm diameter around the corneal centre, and the increase in corneal thickness towards the periphery. The relationship between corneal thickness at these locations and possible associated factors was determined using linear regression models. For this purpose, general and ocular parameters were included., Results: A total of 9729 participants were included in the present analysis (4874 women, age 59.2 ± 10.8 years). Multivariable analysis showed a correlation between the increase in corneal thickness in the circles from 0 to 10 mm (diameter) and the following parameters: age (B = -0.24 µm per year, p < 0.001); body height (B = -0.04 µm, p = 0.005); smoking (B = -0.72 µm, p < 0.001); spherical equivalent (B = -0.70 µm per dioptre, p < 0.001); white-to-white distance (B = -0.75 µm/mm, p < 0.001); mean corneal radius (B = -3.61 µm/mm, p < 0.001); intraocular pressure (B = -0.12 µm/mmHg, p < 0.001); glaucoma (B = -1.94 µm, p < 0.001); and pseudophakia (B = 0.89 µm, p < 0.001)., Conclusion: The results of the present study suggest that several general and ocular parameters are associated with peripheral corneal thickness. In the context of diagnosing glaucoma, a smaller increase in corneal thickness towards the periphery might be a new additional marker., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD)., Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June-31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case-control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted., Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer ( n = 221), followed by ChadOx1/AstraZeneca ( n = 57), mRNA-1273/Moderna ( n = 21), and Ad26.COV2.S/Johnson & Johnson ( n = 11; unknown n = 22). Our case-control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60-1.45, p = 0.75) in connection with a vaccination within a 4-week window., Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk.

Background: The current study aims to identify the relationships between coagulation factors and plasma thrombin generation in a large population-based study by comparing individuals with a history of arterial or venous thrombosis to cardiovascular healthy individuals., Methods: This study comprised 502 individuals with a history of arterial disease, 195 with history of venous thrombosis and 1402 cardiovascular healthy individuals (reference group) from the population-based Gutenberg Health Study (GHS). Calibrated Automated Thrombography was assessed and coagulation factors were measured by means of BCS XP Systems. To assess the biochemical determinants of TG variables, a multiple linear regression analysis, adjusted for age, sex and antithrombotic therapy, was conducted., Results: The lag time, the time to form the first thrombin, was mainly positively associated with the natural coagulant and anti-coagulant factors in the reference group, i.e. higher factors result in a longer lag time. The same determinants were negative for individuals with a history of arterial or venous thrombosis, with a 10 times higher effect size. Endogenous thrombin potential, or area under the curve, was predominantly positively determined by factor II, VIII, X and IX in all groups. However, the effect sizes of the reported associations were 4 times higher for the arterial and venous disease groups in comparison to the reference group., Conclusion: This large-scale analysis demonstrated a stronger effect of the coagulant and natural anti-coagulant factors on the thrombin potential in individuals with a history of arterial or venous thrombosis as compared to healthy individuals, which implicates sustained alterations in the plasma coagulome in subjects with a history of thrombotic vascular disease, despite intake of antithrombotic therapy., (© 2022. The Author(s).)

The prevalence of liver disease, and especially of advanced liver fibrosis, in the German population is poorly defined. The aim of the study was to explore liver enzymes and surrogate scores of hepatic steatosis and advanced hepatic fibrosis in a population-based cohort study in Germany. In the cross-sectional population-based Gutenberg Health study, data of 14,950 participants enrolled between 2007 and 2012 were captured and analyzed. The distribution of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), fatty liver index (FLI), and Fibrosis-4 (FIB-4) score, as well as the underlying risk factors, were assessed by regression models. Elevated liver enzymes in this population-based sample were seen in 19.9% for ALT, 12.8% for AST, and 14% for GGT. Risk factors for liver disease included alcohol use and the presence of the metabolic syndrome, which were both risk factors associated with increased liver enzymes. The FLI suggested that 37.5% of the population exhibited hepatic steatosis and 1.1% of patients exhibited a FIB-4 above the upper cutoff, while 19.2% were in the intermediate range. Interestingly, advanced fibrosis was significantly more frequent in men compared with women (FIB-4: 1.5% vs. 0.6% [P < 0.0001]; NFS: 3.6% vs. 1.9% [P < 0.0001]). In addition, age was a relevant risk factor for exhibiting a noninvasive surrogate score suggestive of advanced fibrosis in the current study population. Conclusion: Elevated liver enzymes were seen in almost a fifth of the German population. At the population-based level, the prevalence of advanced fibrosis was estimated at 1% in Germany., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Patients with peripheral arterial disease (PAD) benefit from combination therapy with acetylsalicylic acid (ASA, 100 mg, one time per day) plus low-dose rivaroxaban (2.5 mg, two times per day) compared to ASA monotherapy. In particular, major adverse cardiac and limb events were significantly reduced after peripheral endovascular revascularization (EVR). In this pilot study, the platelet activation status in vivo and platelet reactivity in vitro were longitudinally analyzed by flow cytometric assays and calibrated automated thrombography in platelet-rich plasma (PRP) from 10 patients with PAD receiving ASA (100 mg, one time per day) before EVR, ASA plus clopidogrel (75 mg, one time per day) after EVR, and ASA plus rivaroxaban (2.5 mg, two times per day) during a long-term follow-up. Platelet responsiveness to clopidogrel was compared to additional 10 patients with stable PAD and clopidogrel (75 mg, one time per day) monotherapy. ASA plus rivaroxaban treatment resulted in a significantly decreased thrombin peak in PRP for two triggers, namely, low concentration of tissue factor (TF) and thrombin, compared to ASA monotherapy. TF-controlled thrombin generation was additionally characterized by a significantly prolonged lag time in PRP and platelet-free plasma during ASA plus rivaroxaban combination therapy. In comparison, ASA plus clopidogrel treatment presented a significant reduction of the thrombin peak in PRP, which was less pronounced than during subsequent ASA plus rivaroxaban therapy. Platelet responsiveness to clopidogrel was observed for 60% of patients receiving ASA plus clopidogrel and clopidogrel monotherapy, respectively. Blocking of CD36 on the platelet surface further reduced the thrombin peak in PRP induced by TF for all three therapy regimes. Platelet activation in vivo and in response to the GPVI-agonist convulxin or thrombin in vitro was similar, whereas integrin αIIbβ3 activation and α-granule release induced by the PAR-1 activating peptide TRAP-6 were significantly diminished during ASA plus rivaroxaban treatment compared to ASA monotherapy. In conclusion, the data of this pilot study indicate an inhibitory effect of rivaroxaban on the thrombin propagation phase of CD36-sensitive platelet thrombin formation in patients with PAD treated with ASA plus rivaroxaban combination therapy, which is associated with decreased PAR-1 but not thrombin-mediated platelet activation., Competing Interests: CE-K received honoraria for lectures from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi-Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jurk, Rothenaicher, Groß, Rossmann, Weißer, Schmidtmann, Münzel and Espinola-Klein.)

Purpose: To investigate the 5-year cumulative incidence and progression of myopic maculopathy in the general population in Germany and to analyze potential risk factors., Design: The Gutenberg Health Study (GHS) is a population-based cohort study including 15 010 participants aged 35 to 74 years at baseline., Participants: A total of 494 eyes of 323 participants (mean age, 50.2 ± 9.2 years; median, -7.25 diopters [D] myopic refractive error) without myopic maculopathy at baseline and 34 eyes of 27 subjects (mean age, 56.7 ± 9.1 years; median, -8.75 D myopic refractive error) with myopic maculopathy met the inclusion conditions, phakic eyes with spherical equivalent ≤-6 D (baseline), and had gradable fundus photographs at baseline and 5-year follow-up., Methods: Myopic maculopathy incidence and progression were assessed by grading of fundus photographs according to a recent international photographic classification system (META-PM). Multivariable logistic regression analysis was used to assess risk factors for progression of myopic maculopathy., Main Outcome Measures: Estimates for incidence and progression of myopic maculopathy., Results: The 5-year cumulative incidence of myopic maculopathy was 0.3% (95% confidence interval [CI], 0.02-1.99; n = 1). Progression occurred in 17 of 34 eyes (50%) with prior myopic maculopathy over 5 years with 4 changes in category. The most common types of progression were enlargement of diffuse and patchy chorioretinal atrophy; a new pathology was present in 8 eyes. Higher intraocular pressure (IOP) (odds ratio [OR], 1.62; 95% CI, 1.51-1.59; P = 0.035) was associated with progression of myopic maculopathy. Female gender (OR, 5.54; 95% CI, 0.93-32.92; P = 0.060) and higher myopic refractive error (OR, 1.62 per diopter; 95% CI, 0.99-1.49; P = 0.063) showed a tendency toward progression., Conclusions: Incidence of myopic maculopathy is rare in highly myopic eyes in the general population aged 35 to 74 years in Germany. Progression of myopic maculopathy in the German population occurred in 50% of highly myopic eyes. We presented population-based 5-year follow-up data on incidence and progression of myopic maculopathy in Europe., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival (OS). The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE-3-LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease-free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median OS in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE-3-LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE-3. Secondarily resected patients of LICC, CELIM and FIRE-3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Estimating COVID-19 mortality is impeded by uncertainties in cause of death coding. In contrast, age-adjusted excess all-cause mortality is a robust indicator of how the COVID-19 pandemic impacts public health. However, in addition to COVID-19 deaths, excess mortality potentially also reflects indirect negative effects of public health measures aiming to contain the pandemic., Objectives: The study examines whether excess mortality in Germany between January 2020 and July 2021 is consistent with fatalities attributed to COVID-19 or may be partially due to indirect effects of public health measures., Methods: Excess mortality trends for the period from January 2020 to July 2021 were checked for consistency with deaths attributed to COVID-19 in both the German federal states and districts of Rhineland-Palatinate. The expected monthly mortality rates were predicted based on data from 2015-2019, taking into account the population demographics, air temperature, seasonal influenza activity, and cyclic and long-term time trends RESULTS: COVID-19-attributed mortality was included in the 95% prediction uncertainty intervals for excess mortality in 232 of 304 (76.3%) month-state combinations and in 607 of 684 (88.7%) month-district combinations. The Spearman rank correlation between excess mortality and COVID-19-attributed mortality across federal states was 0.42 (95% confidence interval [0.31; 0.53]) and 0.21 (95% confidence interval [0.13; 0.29]) across districts., Conclusions: The good agreement of spatiotemporal excess mortality patterns with COVID-19 attributed mortality is consistent with the assumption that indirect adverse effects from public health interventions to contain the COVID-19 pandemic did not substantially contribute to excess mortality in Germany between January 2020 and July 2021., (© 2021. The Author(s).)

Aims: Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of non-invasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality., Methods and Results: In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N=12 599) and fingertip peripheral arterial tonometry (N=11 125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank <0.05). In multivariable-adjusted Cox regression analyses only baseline pulse amplitude was inversely related to mortality [hazard ratio (HR) per standard deviation increase, 0.86, 95% confidence interval (95% CI), 0.79-0.94; P=0.0009]. After exclusion of individuals with prevalent CVD the association was no longer statistically significant in multivariable-adjusted models (HR 0.91, 95% CI 0.81-1.02; P=0.11). None of the vascular variables substantially increased the C-index of a model comprising clinical risk factors., Conclusions: In our cohort, non-invasive measures of peripheral vascular structure and function did not reveal clinically relevant associations with incident CVD or mortality. Whether determination of pulse amplitude by peripheral arterial tonometry improves clinical decision-making in primary prevention needs to be demonstrated., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Late mortality of European 5-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95% CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95% CI 6.32-6.62). At 60 to 68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95% CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5-20.4) to 7.3% (95% CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P = .1105 and P = .0829, respectively). PanCareSurFup is the largest study with the longest follow-up of late mortality among European childhood and adolescent cancer 5-year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long-term care needs., (© 2021 UICC.)

Introduction: Postoperative sore throat (POST) is a comparatively minor but very common side effect of general anaesthesia with a supraglottic airway device. The patient considers these side effects a mirror of the quality of anaesthesia. The aims of this study are to evaluate gender-specific differences in the incidence of POST and to assess whether the effects of known risk factors vary between genders., Methods and Analysis: The LadyLAMA trial is a single-centre, patient-blinded, randomised controlled trial. Consecutive patients requiring ophthalmological surgery under general anaesthesia with a second generation Ambu AuraGain laryngeal mask are randomly allocated to either cuff pressure of 45 cmH2O or cuff pressure of 60 cmH2O. We estimate the difference in POST between the genders at 20% and we hypothesised that a reduction of cuff pressure would reduce POST by 10%. A total of 800 patients will be recruited, with each subgroup including 200 patients to achieve 80% power for detecting a difference at the 5% significance level. Primary endpoints are gender differences in the incidence of POST within 24 hours postoperatively, as well as comparison of cuff pressure 45 cmH2O to 60 cmH2O with respect to POST. The main secondary objective is the effect of cuff pressure on POST stratified by gender. Further secondary endpoints are gender-specific differences in POST and hoarseness in postanaesthesia care unit (PACU) at 48 and 72 hours (or until freedom of discomfort). The parameter cuff pressure serves as key-secondary endpoint., Ethics and Dissemination: The project is approved by the local ethics committee of the Medical Association of the Rhineland Palatine state (Nr. 2021-15835). The results of this study will be made available in the form of manuscripts for publication and presentations at national and international meetings., Trial Registration Number: NCT04915534., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Unselected data of nationwide studies of hospitalized patients with COVID-19 are still sparse, but these data are of outstanding interest to avoid exceeding hospital capacities and overloading national healthcare systems. Thus, we sought to analyze seasonal/regional trends, predictors of in-hospital case-fatality, and mechanical ventilation (MV) in patients with COVID-19 in Germany. We used the German nationwide inpatient samples to analyze all hospitalized patients with a confirmed COVID-19 diagnosis in Germany between 1 January and 31 December in 2020. We analyzed data of 176,137 hospitalizations of patients with confirmed COVID-19-infection. Among those, 31,607 (17.9%) died, whereby in-hospital case-fatality grew exponentially with age. Overall, age ≥ 70 years (OR 5.91, 95%CI 5.70-6.13, p < 0.001), pneumonia (OR 4.58, 95%CI 4.42-4.74, p < 0.001) and acute respiratory distress syndrome (OR 8.51, 95%CI 8.12-8.92, p < 0.001) were strong predictors of in-hospital death. Most COVID-19 patients were treated in hospitals in urban areas ( n = 92,971) associated with the lowest case-fatality (17.5%), as compared to hospitals in suburban (18.3%) or rural areas (18.8%). MV demand was highest in November/December 2020 (32.3%, 20.3%) in patients between the 6th and 8th age decade. In the first age decade, 78 of 1861 children (4.2%) with COVID-19-infection were treated with MV, and five of them died (0.3%). The results of our study indicate seasonal and regional variations concerning the number of COVID-19 patients, necessity of MV, and case fatality in Germany. These findings may help to ensure the flexible allocation of intensive care (human) resources, which is essential for managing enormous societal challenges worldwide to avoid overloaded regional healthcare systems.

Purpose: The purpose of this study was to investigate the association between intraocular pressure (IOP) and ocular geometry., Methods: The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Study participants underwent a comprehensive ophthalmologic examination including noncontact tonometry, objective refraction, optical biometry, and Scheimpflug imaging of the anterior segment at the first 5-year follow-up examination (in 2012-2017). Multivariable linear regression analysis was carried out to determine associations of IOP and geometric parameter of the human phakic eye, namely central corneal thickness (CCT), corneal curvature, anterior chamber depth (ACD), lens thickness, and axial length. In addition, the relationship of IOP and the anterior chamber angle (ACA) width was analyzed., Results: There were 6640 participants with phakia (age 57.3 ± 10.2 years, 49.1% women) that were included in this cross-sectional analysis. Mean IOP was 14.8 ± 2.9 mm Hg in the right eyes and 14.9 ± 2.9 mm Hg in the left eyes. IOP increased with higher CCT, greater posterior segment length, higher age (all P < 0.001), thicker lens (P = 0.003), and female sex (P = 0.05), whereas the ACD was not associated with higher IOP. The IOP increased with a narrower ACA in univariable analysis (P < 0.001), but not in adjusted analysis in subjects with an open angle., Conclusions: IOP values are related to ocular geometry, as shown in this population-based study on Caucasian subjects. Thus, knowledge of the architecture of the eye is an important factor when measuring IOP. Longitudinal evaluation will analyze whether some of these parameters are also risk factors for the development of glaucoma.

Background: COPD is an established predictor of clinical outcome in patients with chronic heart failure (HF). However, little evidence is available about the predictive value of FEV 1 in chronic HF., Research Question: Is pulmonary function related to the progression of chronic HF?, Study Design and Methods: The MyoVasc study (ClinicalTrials.gov Identifier: NCT04064450) is a prospective cohort study of HF. Information on pulmonary and cardiac functional and structural status was obtained by body plethysmography and echocardiography. The primary study end point was worsening of HF., Results: Overall 2,998 participants (age range, 35-84 years) with available FEV 1 data were eligible for analysis. Linear multivariate regression analysis revealed an independent relationship of FEV 1 (per -1 SD) with deteriorated systolic and diastolic left ventricle (LV) function as well as LV hypertrophy under adjustment of age, sex, height, cardiovascular risk factors (CVRFs), and clinical profile (LV ejection fraction: β-estimate, -1.63% [95% CI, -2.00% to -1.26%]; E/E' ratio: β-estimate, 0.82 [95% CI, 0.64-0.99]; and LV mass/height 2.7 : β-estimate, 1.58 [95% CI, 1.07-2.10]; P < .001 for all). During a median time to follow-up of 2.6 years (interquartile range, 1.1-4.1 years), worsening of HF occurred in 235 individuals. In Cox regression model adjusted for age, sex, height, CVRF, and clinical profile, pulmonary function (FEV 1 per -1 SD) was an independent predictor of worsening of HF (hazard ratio [HR], 1.44 [95% CI, 1.27-1.63]; P < .001). Additional adjustment for obstructive airway pattern and C-reactive protein mitigated, but did not substantially alter, the results underlining the robustness of the observed effect (HR FEV1 , 1.39 [95% CI, 1.20-1.61]; P < .001). The predictive value of FEV 1 was consistent across subgroups, including individuals without obstruction (HR, 1.55 [95% CI, 1.34-1.77]; P < .001) and nonsmokers (HR, 1.72 [95% CI, 1.39-1.96]; P < .001)., Interpretation: FEV 1 represents a strong candidate to improve future risk stratification and prevention strategies in individuals with chronic, stable HF., Trial Registry: ClinicalTrials.gov; No.: NCT04064450; URL: www.clinicaltrials.gov., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Age-related macular degeneration (AMD) is a major cause of visual impairment and blindness. This study evaluates the incidence and progression of AMD in a large German cohort., Methods: The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany that includes 15,010 participants between 35 and 74 years of age. The baseline examination, including fundus photography, was conducted between 2007 and 2012, and the 5-year follow-up examination was performed between 2012 and 2017. AMD grading of fundus photographs was performed according to the Rotterdam Eye Study classification. The 5-year cumulative incidence and progression of AMD were calculated. Poisson regression analysis was conducted to investigate factors associated with the cumulative incidence and progression of AMD., Results: Six-thousand-eight-hundred-eighty-eight participants (49.8%, n = 3427 female) were included in the analysis. AMD prevalence was 8.5% [95% CI: 7.9-9.2%] at baseline and 10.3% [95% CI: 9.6-11.1%] at follow-up. The cumulative 5-year-incidence was 2.0% [1.7-2.4%]. AMD progression within 5 years was seen in 18.1% [95% CI: 15.1-21.5%] of the participants. AMD incidence and AMD progression were associated with higher age, for each 10-year increase in age, the risk of AMD doubles (RR = 2.30), and the risk of progression of the disease is increased by 1.6. while AMD incidence also with pseudophakic status., Conclusions: In summary, this population-based sample provides substantial epidemiologic data from a large German cohort, including data on progression and cumulative incidence of macular degeneration in younger age groups. AMD progression over 5 years is common in the German population, 18.1% of subjects with AMD showed progression in at least one eye in this time frame and is associated with higher age. Nevertheless, although usually defined to occur over the age of 50, in this cohort AMD occurred in 0.5% and AMD progression occurred in 5.4% of those already affected in the youngest age group before 50 years of age., (© 2021. The Author(s).)

Purpose: Hypersensitivity is a frequent complaint in children with molar incisor hypomineralisation (MIH). This double-blind randomised controlled trial aimed to evaluate non-inferiority in hypersensitivity relief of a toothpaste containing microcrystalline hydroxyapatite compared to amine fluoride in children with MIH., Materials and Methods: Children were randomised into 2 groups: either hydroxyapatite (intervention) or amine fluoride toothpaste (control). The primary endpoint was pain sensation in response to tactile stimulus (Wong-Baker FACES Pain Rating Scale) 56 days after randomisation and analysed by mixed effects linear regression analysis. Non-inferiority was inferred if the upper limit of the one-sided 95% confidence interval (CI) of the difference between intervention and control group was below the non-inferiority margin of 1 in the ITT (intention-to-treat) and PP (per protocol) population., Results: Twenty-one children were randomised and 14 children finished the study per protocol. In the ITT population, hydroxyapatite was non-inferior to amine fluoride (mean difference: -0.75 95%CI [-∞;0.49]). In the PP population, non-inferiority could not be shown (-0.62 [-∞;1.08])., Conclusions: Overall non-inferiority in hypersensitivity relief of a toothpaste containing hydroxyapatite compared to amine fluoride could not be shown. However, the hydroxyapatite group tended to be less hypersensitive in both populations. Attrition of the PP population due to the COVID-19 pandemic led to loss of statistical power.

In the vertebrate cochlea, the reticular lamina seals the organ of Corti against the endolymph filled scala media. After noise exposure, fast alterations in the endothelial nitric oxide synthase (eNOS) expression level were identified in this cochlear structure. Minor amounts of nitric oxide (NO) produced by eNOS or applied by NO donors such as S-nitroso- N -acetyl-penicillamine (SNAP) might protect this vulnerable part of the organ of Corti, on the line of gap junctions of supporting cells and cochlear microcirculation. In n =5 anesthetized guinea pigs, SNAP was intravenously applied in two concentrations. Six untreated animals served as controls. The cochleae were removed and prepared for immunoelectron microscopy using specific gold-labeled anti-eNOS antibodies. The density of the gold particles was quantified for seven cellular regions in the reticular lamina at the ultrastructural level. Following SNAP application, a significant increase in eNOS expression (+176%) was detected compared with controls ( p =0.012). The increase occurred mainly in actin-rich cuticular structures and the prominent microtubules bundles. Correlation analysis revealed three clear and five moderate cellular associations for controls, whereas only one clear and one moderate after SNAP application. Thus, application of the NO donor SNAP resulted in an increase in eNOS expression in distinct regions of the reticular lamina.

This retrospective pilot study used a newly developed evaluation tool to assess the prevalence and incidence of White Spot Lesions (WSL) before and after multibracket appliance (MB) therapy. Digital photographs of 121 adolescent patients (63 ♂, 58 ♀) with metal brackets were analyzed retrospectively before and after MB therapy. The labial surfaces of anterior teeth, canine teeth, and premolars in the upper (UJ) and lower jaws (LJ) were evaluated using the Enamel Decalcification Index (EDI) by Banks and Richmond (Eur J Orthod, 16(1):19-25, 1994, levels 0-3) and a specially developed digitally scaled graticule with concentric circles to quantify the extent of WSL (in %). The statistical data analysis was based on crosstabulations and logistic regression. Before MB, 69.4% of the patients presented at least one WSL and 97.5% after, an increase of 28.1%. Before MB, 18.4% of the tooth surfaces (TS) showed an EDI level of 1-3. After MB, 51.8% of the TS featured WSL. 18.2% of the TS showed a WSL to the extent of ≥ 20-100% before and 52.3% after MB. The incidence in the UJ (71-79%) as well as the LJ (64-76%) was highest for the first and second premolars and lowest for LJ incisors (22-35%). The probability for developing a new distal WSL is higher than developing gingival, mesial or occlusal WSL. Labial MB therapy drastically increases the risk of developing WSL. We verified a concise quantification of the extent of labial WSL with the evaluation index., (© 2021. The Author(s).)

Aim: To investigate short- and long-term intraocular pressure (IOP) fluctuations and further ocular and demographic parameters as predictors for normal tension glaucoma (NTG) progression., Methods: This retrospective, longitudinal cohort study included 137 eyes of 75 patients with NTG, defined by glaucomatous optic disc or visual field defect with normal IOP (<21 mm Hg), independently from therapy regimen. IOP fluctuation, mean, and maximum were inspected with a mean follow-up of 38mo [standard deviation (SD) 18mo]. Inclusion criteria were the performance of minimum two 48-hour profiles including perimetry, Heidelberg retina tomograph (HRT) imaging, and optic disc photographs. The impact of IOP parameters, myopia, sex, cup-to-disc-ratio, and visual field results on progression of NTG were analyzed using Cox regression models. A sub-group analysis with results from optical coherence tomography (OCT) was performed., Results: IOP fluctuations, average, and maximum were not risk factors for progression in NTG patients, although maximum IOP at the initial IOP profile was higher in eyes with progression than in eyes without progression ( P =0.054). The 46/137 (33.5%) eyes progressed over the follow-up period. Overall progression (at least three progression confirmations) occurred in 28/137 eyes (20.4%). Most progressions were detected by perimetry (36/46). Long-term IOP mean over all pressure profiles was 12.8 mm Hg (SD 1.3 mm Hg); IOP fluctuation was 1.4 mm Hg (SD 0.8 mm Hg). The progression-free five-year rate was 58.2% (SD 6.5%)., Conclusion: Short- and long-term IOP fluctuations do not result in progression of NTG. As functional changes are most likely to happen, NTG should be monitored with visual field testing more often than with other devices., (International Journal of Ophthalmology Press.)

Introduction: Rapid sequence induction of anaesthesia is indicated in patients with an increased risk of pulmonary aspiration. The main objective of the technique is to reduce the critical time period between loss of airway protective reflexes and rapid inflation of the cuff of the endotracheal tube to minimise the chance of aspiration of gastric contents. The COVID-19 pandemic has reinforced the importance of first-pass intubation success to ensure patient and healthcare worker safety. The aim of this study is to compare the first-pass intubation success rate (FPS) using the videolaryngoscopy compared with conventional direct laryngoscopy in surgical patients with a high risk of pulmonary aspiration., Methods and Analysis: The LARA trial is a multicentre, patient-blinded, randomised controlled trial. Consecutive patients requiring tracheal intubation are randomly allocated to either the McGrath MAC videolaryngoscope or direct laryngoscopy using the Macintosh laryngoscope. The expected rate of FPS is 92% in the McGrath group and 82% in the Macintosh group. Each group must include a total of 500 patients to achieve 90% power for detecting a difference at the 5% significance level. Successful intubation with the FPS is the primary endpoint. The secondary endpoints are the time to intubation, the number of intubation attempts, the necessity of airway management alternatives, the visualisation of the glottis using the Cormack and Lehane Score and the Percentage Of Glottic Opening Score and definite adverse events., Ethics and Dissemination: The project is approved by the local ethics committee of the Medical Association of the Rhineland Palatine state (registration number: 2020-15502) and medical ethics committee of the University of Freiburg (registration number: 21-1303). The results of this study will be made available in form of manuscripts for publication and presentations at national and international meetings., Trial Registration: NCT04794764., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Neonates and young infants with diagnosed or highly suspected glaucoma require an examination under anaesthesia to achieve accurate intraocular pressure (IOP) measurements, since crying or squinting of the eyes may increase IOP and lead to falsely high values. IOP considerably depends on perioperative variables such as haemodynamic factors, anaesthetics, depth of anaesthesia and airway management. The aim of this paper is to report the design and baseline characteristics of EyeBIS, which is a study to develop a standardised anaesthetic protocol for the measurement of IOP under anaesthesia in childhood glaucoma, by investigating the link between the magnitude of IOP and depth of anaesthesia., Methods and Analysis: This is a single-centre, prospective cohort study in 100 children with diagnosed or highly suspected glaucoma all undergoing ophthalmological examination under general anaesthesia. 20 children, who undergo general anaesthesia for other reasons, are included as controls. The primary outcome measure is the establishment of a standardised anaesthetic protocol for IOP measurement in childhood glaucoma by assessing the relationship between IOP and depth of anaesthesia (calculated as an electroencephalography variable, the bispectral index), with special emphasis on airway management and haemodynamic parameters. The dependence of IOP under anaesthesia on airway management and haemodynamic parameters will be described, using a mixed linear model. Restricting the model to patients with healthy eyes will allow to determine a 95% reference region, in which 95% of the measurement values of patients with healthy eyes can be expected., Ethics and Dissemination: The study has been approved by the local ethics committee of the Medical Association of Rhineland-Palatine (Ethik-Kommisssion der Landesaerztekammer Rheinland-Pfalz), Germany (approval number: 2019-14207). This work will be disseminated by publication of peer-reviewed manuscripts, presentation in abstract form at national and international scientific meetings and data sharing with other investigators., Trial Registration Number: ClinicalTrials.gov Registry (NCT03972852)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We aimed to determine the prevalence of corneal arcus and to identify associated factors in the general population of Germany., Methods: The Gutenberg Health Study (GHS) is a population-based cohort study in Germany, which includes an ophthalmological assessment. Refraction, distance-corrected visual acuity, non-contact tonometry and anterior segment imaging were performed for the five-year follow-up examination. Anterior segment photographs were graded for the presence of corneal arcus. Prevalence estimates were computed, and multivariable logistic regression analysis was applied to determine associated factors for corneal arcus including sex, age, spherical equivalent, central corneal thickness, intraocular pressure (IOP), socio-economic status, smoking, BMI, systolic and diastolic arterial blood pressure, HbA1c, HDL-C, LDL-C, triglyceride, and lipid modifying agents., Results: A total of 9,850 right and 9,745 left eyes of 9,858 subjects (59.2±10.8 years), 49.0% females were included in this cross-sectional analysis. 21.1% of men (95%-CI: 20.0%- 22.3%) had a corneal arcus in at least one eye, and 16.9% (95%-CI: 15.9%- 18.0%) of women. In multivariable analyses, the presence of corneal arcus was associated with male gender (OR = 0.54 for female, p<0.0001), higher age (OR = 2.54 per decade, p<0.0001), smoking (OR = 1.59, p<0.0001), hyperopia (OR = 1.05 per diopter, p<0.0001), thinner cornea (OR = 0.994 per μm, p<0.0001), higher IOP (OR = 1.02, p = 0.039), higher HDL-C-level (OR = 2.13, p<0.0001), higher LDL-C-level (OR = 1.21, p<0.0001), and intake of lipid modifying agents (OR = 1.26, p = 0.0001). Arcus was not associated with socio-economic status, BMI, arterial blood pressure, and HbA1c., Conclusions: Corneal arcus is a frequent alteration of the cornea in Germany and is associated with ocular parameters and systemic parameters of dyslipidemia., Competing Interests: Funding from commercial sources: Boehringer Ingelheim; PHILIPS Medical Systems, Allergan, Bayer Vital, Novartis, PlusOptix, and Heidelberg Engineering. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe., Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555)., Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran., Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation., Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim., Competing Interests: Declaration of interests FAK reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharpe & Dohme, the Netherlands Organisation for Health Research and Development, Actelion, the Dutch Heart foundation, and the Dutch Thrombosis Association, all outside the submitted work. SB reports congress and travel payments from Daiichi Sankyo and Bayer; honoraria from BTG Pharmaceuticals, Boston Scientific, Bayer HealthCare, and LeoPharma; and institutional grants from Sanofi, all outside the submitted work. WA reports research support from Bayer, and participating in advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, Portola, Janssen, Aspen, and Sanofi all outside the submitted work. MB reports consulting and speaker fees from Bayer Healthcare, Daiichi Sankyo, and Sanofi Aventis outside the submitted work. FC reports research grant support from Bristol-Myers Squibb-Pfizer Alliance; fees for board memberships or symposia from Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Astra Zeneca; and travel support from Bayer, Bristol-Myers Squibb-Pfizer Alliance, Leo Pharma, and Actelion all outside the submitted work. KD reports unrestricted research support and speaker or consultant fees from Janssen outside the submitted work. DD reports speaker's honoraria from Bayer Vital, Daiichi Sankyo, and Bristol-Myers Squibb-Pfizer Alliance; and consulting fees from Bayer Vital and Daiichi Sankyo all outside the submitted work. KE reports lecture fees from AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, and Novartis; and consulting fees from Bayer Vital, Boehringer Ingelheim, Novartis, and Novo Nordisk all outside the submitted work. GG reports personal fees or research grants, or both, from Bayer, Boehringer Ingelheim, Leo, Merck Sharpe & Dohme, and Pfizer outside the submitted work. MVH reports grants from the ZonMW Dutch Healthcare Fund; and grants and personal fees to the Leiden University Medical Center from Boehringer Ingelheim, Bristol-Myers Squibb-Pfizer Alliance, Bayer Health Care, Aspen, and Daiichi Sankyo, all outside the submitted work. DJ reports serving as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; serving as a speaker or a member of a speakers' bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo Pharma, ROVI, and Sanofi; and receiving grants for clinical research from Daiichi Sankyo, Sanofi, and ROVI all outside the submitted work. MK reports speaker fees from Pfizer, Boehringer Ingelheim, and Bayer outside the submitted work. IML reports receiving consulting fees and research grants from, and being a member of scientific advisory boards for AOPOrphan Pharmaceuticals, Actelion-Janssen, Merck Sharpe & Dohme, United Therapeutics, Medtronic, Neutrolis, and Ferrer, in addition to being an investigator in trials involving these companies. ML reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi Sankyo, Merck Sharpe & Dohme, and Bristol-Myers Squibb-Pfizer Alliance; and project funding from Thermo Fisher Scientific all outside the submitted work. NM reports consulting fees, speaker fees, and project funding from Bayer and Bristol-Myers Squibb-Pfizer Alliance; speaker fees from AstraZeneca and Boehringer Ingelheim; and consulting fees from Abbott and Terumo all outside the submitted work. AOP reports speaker fees from SC Pfizer Romania, Servier Pharma, Novartis Pharma Services Romania, Bayer, and SC Sanience outside the submitted work. AS reports consulting fees from Pfizer outside the submitted work. SS reports consulting fees and speaker fees from Aspen and Boehringer Ingelheim; speaker fees from Bayer and Daiichi Sankyo; and project funding and speaker fees from Bristol-Myers Squibb-Pfizer Alliance all outside the submitted work. K-HS reports speaker and consulting fees from Merck Sharpe & Dohme, Janssen-Cilag, and Abbott outside the submitted work. FV reports research grants from Daiichi Sanyo, Boehringer-Ingelheim, Radiometer, and Biomerieux, outside the submitted work. SVK reports institutional research grants and personal consultancy or speaker fees from Actelion/Janssen, Bayer, Daiichi Sankyo, and Boston Scientific; institutional research grants from Boehringer Ingelheim and Servier; and personal consultancy or speaker fees from Bristol-Myers Squibb-Pfizer Alliance and Novartis all outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Lung cancer is the most common oncological cause of death in the Western world. Early diagnosis is critical for successful treatment. However, no effective screening methods exist. A promising approach could be the use of volatile organic compounds as diagnostic biomarkers. To date there are several studies, in which dogs were trained to discriminate cancer samples from controls. In this study we evaluated the abilities of specifically trained dogs to distinguish samples derived from lung cancer patients of various tumor stages from matched healthy controls., Methods: This single center, double-blind clinical trial was approved by the local ethics committee, project no FF20/2016. The dog was conditioned with urine and breath samples of 36 cancer patients and 150 controls; afterwards, further 246 patients were included: 41 lung cancer patients comprising all stages and 205 healthy controls. From each patient two breath and urine samples were collected and shock frozen. Only samples from new subjects were presented to the dog during study phase randomized, double-blinded. This resulted in a specific conditioned reaction pointing to the cancer sample., Results: Using a combination of urine and breath samples, the dog correctly predicted 40 out of 41 cancer samples, corresponding to an overall detection rate of cancer samples of 97.6% (95% CI [87.1, 99.9%]). Using urine samples only the dog achieved a detection rate of 87.8% (95% CI [73.8, 95.9%]). With breath samples, the dog correctly identified cancer in 32 of 41 samples, resulting in a detection rate of 78% (95% CI [62.4, 89.4%])., Conclusions: It is known from current literature that breath and urine samples carry VOCs pointing to cancer growth. We conclude that olfactory detection of lung cancer by specifically trained dogs is highly suggestive to be a simple and non-invasive tool to detect lung cancer. To translate this approach into practice further target compounds need to be identified., (© 2021. The Author(s).)

Aims: The number of transcatheter mitral valve repair (TMVr) procedures has increased substantially during the last years. A better understanding of the relationship between hospital volume of transcatheter transvenous mitral valve repairs using MitraClip® and patient outcomes may provide information for future policy decisions to improve patient management., Methods and Results: We analysed patient characteristics and in-hospital outcomes for all TMVr procedures using MitraClip® performed in Germany from 2011 to 2017. Hospitals were stratified according to centre volumes and patients were compared for baseline characteristics and adverse in-hospital events. Overall, 24 709 inpatients were treated during the observational period. Patients treated in centres with a volume of ≤10 procedures annually developed more often pulmonary embolism (odds ratio 2.22, 95% confidence interval 1.19-4.13; P = 0.012) compared to those treated in centres with a volume of >10 procedures annually, whereas no association of centre volume (≤10 or >10) was found with in-hospital mortality (P = 0.728). Although patients treated in centres with an annual volume >25 TMVr procedures had higher numbers of comorbidities compared to those treated in centres with an annual volume of ≤25 TMVr procedures, in-hospital mortality did not differ (3.6% vs. 3.5%, P = 0.485). Similarly, when centre volumes were stratified for ≤50 vs. >50 procedural volumes, no association with in-hospital mortality was recorded (P = 0.792). A lower rate of mitral valve surgery after MitraClip® was observed over time, particularly in high-volume centres., Conclusion: Annual numbers of MitraClip® implantations increased from 2011 to 2017 in Germany, whereas in-hospital mortality remained stable. Although patients treated in high-volume centres had a more unfavourable risk profile, in-hospital mortality was comparable to that of low-volume centres., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In neonatologic clinical practice and research the percentage of fetal hemoglobin (HbF) of total hemoglobin can be of interest. Blood gas analyzers offer the measurement of HbF. However, it is not known if results are accurate enough to apply in clinical decision-making or scientific questions. In this prospective diagnostic study, we examined the accuracy of HbF measurement by a blood gas analyzer., Methods: On a neonatal intensive care and neonatal ward, the percentage of HbF was measured using both the laboratory gold standard (HbFlab, reference method) and the blood gas analyzer (HbFgas) (ABL 800 Flex, Radiometer). Agreement of HbFlab and HbFgas was assessed by the Bland-Altman method including bias and limits of agreement and by calculation of the root mean square error (RMSE)., Results: Thirty-five measurements in 23 term and preterm infants with a median body weight of 2190 g (min-max 967-3800 g) and a median postmenstrual age of 36+1 weeks (min-max 29+6-43+2) were performed. The Bland-Altman diagram for the measurement of HbF(gas) versus HbF(lab) shows an overestimation of HbF by the blood gas analyzer (bias 9.3%, limits of agreement 1 to 17.6%). RMSE was 10.2%; 45.7% of HbFgas measurements were >10% out of range from HbFlab. There was no influence of age, body temperature or oxygen saturation on the bias (p=0,132; p=0,194; p=0,970), but bias increased with increasing HbFlab (Pearson correlation r=0,426; p=0,011)., Conclusion: The measurement of HbF in term and preterm infants by a blood gas analyzer lacked sufficient agreement with that of the reference method to recommend this application for clinical decision-making or scientific purposes., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort. Methods and results: 15,010 participants (aged 35-74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit and resistance arteries was determined by flow-mediated dilation (FMD) of the brachial artery, reactive hyperemia index (RHI) using peripheral arterial tonometry, as well as by reflection index (RI) derived from digital photoplethysmography, respectively. Among all subjects, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Mean cumulative smoking exposure was 22.1 ± 18.1 pack-years in current smokers and mean years since quitting was 18.9 ± 12.7 in former smokers. In multivariable linear regression models adjusted for typical confounders, smoking status, pack-years of smoking, and years since quitting smoking were independently associated with RHI and RI, while no association was found for FMD. Overall, no clear dose-dependent associations were observed between variables, whereby higher exposure tended to be associated with pronounced resistance artery endothelial dysfunction. Conclusions: Cigarette smoking is associated with altered endothelial function of resistance, but not conduit arteries. The present results suggest that smoking-induced endothelial dysfunction in different circulatory beds may exhibit a differential picture., Competing Interests: TM and PW are PI's of the DZHK, Partner Site Rhine-Main, Mainz, Germany. PW and JP are funded by the Federal Ministry of Education and Research (BMBF 01EO1503). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hahad, Arnold, Prochaska, Panova-Noeva, Schulz, Lackner, Pfeiffer, Schmidtmann, Michal, Beutel, Wild, Keaney, Daiber and Münzel.)

Glomerular filtration rate (GFR) declines with age by approx. 1 ml/min/m 2 per year beginning in the third decade of life. At 70 years of age > 40 ml/min/m 2 of GFR will be lost. Thus, factors affecting loss of GFR have significant public health implications. Furthermore, the definition of chronic kidney disease based on GFR may not be appropriate for the elderly. We analyzed factors affecting absolute and relative change of eGFR over a 5 year period in 12,381 participants of the Gutenberg Health Study. We estimated GFR at baseline and after 5 years of follow-up by two different equations. Association with the decline of estimated GFR (eGFR) was assessed by multivariable regression analysis. We confirmed a median loss of eGFR per year of approx. 1 ml/min/m 2 . Aside from albuminuria systolic blood pressure was most strongly associated with faster decline of eGFR followed by echocardiographic evidence of left ventricular diastolic dysfunction and reduced ejection fraction. White blood cell count showed a moderate association with eGFR loss. Diastolic blood pressure, serum uric acid and serum albumin were associated with slower GFR decline in multivariable analysis. Sensitivity analysis with exclusion of individuals taking diuretics, antihypertensive, antidiabetic, or lipid lowering drugs confirmed these associations.

Aims: Catheter-directed treatment of acute pulmonary embolism (PE) is technically advancing. Recent guidelines acknowledge this treatment option for patients with overt or imminent haemodynamic decompensation, particularly when systemic thrombolysis is contraindicated. We investigated patients with PE who underwent catheter-directed thrombolysis (CDT) in the German nationwide inpatient cohort., Methods and Results: Data from hospitalizations with PE (International Classification of Disease code I26) between 2005 and 2016 were collected by the Federal Office of Statistics in Germany. Patients with PE who underwent CDT (OPS 8-838.60 or OPS code 8-83b.j) were compared with patients receiving systemic thrombolysis (OPS code 8-020.8), and those without thrombolytic or other reperfusion treatment. The analysis was not prespecified; therefore, our findings can only be considered to be hypothesis generating. We analysed data from 978 094 hospitalized patients with PE. Of these, 41 903 (4.3%) patients received thrombolytic treatment [systemic thrombolysis in 4.2%, CDT in 0.1% (1175 patients)]. Among patients with shock, CDT was associated with lower in-hospital mortality compared to systemic thrombolysis [odds ratios (OR) 0.30 (95% 0.14-0.67); P = 0.003]. Intracranial bleeding occurred in 14 (1.2%) patients who received CDT. Among haemodynamically stable patients with right ventricular dysfunction (intermediate-risk PE), CDT also was associated with a lower risk of in-hospital mortality compared to systemic thrombolysis {OR 0.55 [95% confidence interval (CI) 0.40-0.75]; P < 0.001} or no thrombolytic treatment [0.45 (95% CI 0.33-0.62); P < 0.001]., Conclusion: In the German nationwide inpatient cohort, based on administrative data, CDT was associated with lower in-hospital mortality rates compared to systemic thrombolysis, but the overall rate of intracranial bleeding in patients who received CDT was not negligible. Prospective controlled data are urgently needed to determine the true value of this treatment option in acute PE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Portal vein tumor thrombosis (PVTT) is a frequent complication of hepatocellular carcinoma (HCC), which leads to classification as advanced stage disease (regardless of the degree of PVTT) according to the Barcelona Clinic Liver Cancer Classification. For such patients, systemic therapy is the standard of care. However, in clinical reality, many patients with PVTT undergo different treatments, such as resection, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), or best supportive care (BSC). Here we examined whether patients benefited from such alternative therapies, according to the extent of PVTT., Methods: This analysis included therapy-naïve patients with HCC and PVTT treated between January 2005 and December 2016. PVTT was classified according to the Liver Cancer study group of Japan as follows: Vp1 = segmental PV invasion; Vp2 = right anterior or posterior PV; Vp3 = right or left PV; Vp4 = main trunk. Overall survival (OS) was analyzed for each treatment subgroup considering the extent of PVTT. We performed Cox regression analysis with adjustment for possible confounders. To further attenuate selection bias, we applied propensity score weighting using the inverse probability of treatment weights., Results: A total of 278 treatment-naïve patients with HCC and PVTT were included for analysis. The median observed OS in months for each treatment modality (resection, TACE/SIRT, sorafenib, BSC, respectively) was 32.4, 8.1, N/A, and 1.7 for Vp1; 10.7, 6.9, 5.5, and 1.2 for Vp2; 6.6, 7.5, 2.9, and 0.6 for Vp3; and 8.0, 3.6, 5.3, and 0.7 for Vp4. Thus, the median OS in the resection group in case of segmental PVTT (Vp1) was significantly longer compared to any other treatment group (all p values <0.01)., Conclusions: Treatment strategy for HCC with PVTT should not be limited to systemic therapy in general. The extent of PVTT should be considered when deciding on treatment alternatives. In patients with segmental PVTT (Vp1), resection should be evaluated., Competing Interests: The authors have declared that no competing interests exist.

Background: Patient blood management programs should be applied to the pediatric population, but little is known about the current transfusion practice of pediatric burn injury patients. This retrospective study was performed to evaluate the practice of red blood cell (RBC) transfusion in children with burn injury, their predictive factors, and adherence to the German transfusion guideline., Methods: We reviewed the RBC transfusion practice of all children younger than 8 years with burn injury who were operated during a four-year period in a German university medical center. We analyzed the data associated with transfusion and guideline conformity of transfusion triggers for RBCs from the beginning to the end of hospital stay using logistic regression., Results: During the four-year period, 138 children (median age 21 months, minimum-maximum 9-101 months) with burn injury needed surgery, 31 children were transfused with RBCs. During their hospital stay, the median hemoglobin concentrations (Hb) of transfused and non-transfused children were 8 g/dL (6.3-11.3 g/dL) and 10.7 (7-13.8 g/dL), respectively. Total body surface area burned (TBSA) (OR = 1.17 per % TBSA, 95% CI = [1.05; 1.30], p = 0.0056), length of surgery (OR = 1.016 per minute, 95% CI = [1.003; 1.028], p = 0.0150), and Hb (OR = 0.48 per 1 g/dl in Hb, 95% CI = [0.24; 0.95], p = 0.0343) were associated with transfusion while other factors (age, gender, ASA, and catecholamines) did not show notable association. Length of stay was mainly influenced by TSBA (+ 1.38 days per %, p <  0.0001), age (+ 0.21 days per month, p = 0.0206), and administering of catecholamines (+ 14.3 days, p = 0.0118), but not by RBC transfusion. The decision to transfuse was in 23% too restrictive and in 74% too liberal according to the German guidelines., Conclusions: Amount of TBSA, length of surgery, and Hb influenced the RBC transfusion rate in burned children. However, age and length of stay were not affected by transfusion of RBCs. In clinical practice of burned children, physicians follow a more liberal transfusion strategy than the proposed in guidelines.

Regarding their resistance five sealants were tested in vitro after experiencing mechanical, thermal and chemical stress. Included for testing were two fluoride varnishes: Fluor Protector [FP] (Ivoclar Vivadent) and Protecto CaF2 Nano One-Step Seal [PN] (BonaDent) and three fluoride-composite filled sealants (with acid etch technique): Clinpro XT Varnish [CP] (3 M Espe), Pro Seal [PS] & Light Bond [LB] (Reliance Orthodontic Products) and a positive control group [CG] Tetric EvoFlow (Ivoclar Vivadent). The sealants were applied on 180 bovine teeth (n = 10/ sealer) in a standardized manner after bracket bonding. Mechanical pressure and its effect by simulating different time points and standardized electric cleaning protocol was tested first. Followed by thermal burden due to varying thermal stress and thirdly change in pH stress imitating chemical exposure were examined separately. A digital microscope and a grid incisal and apical to the brackets (n = 32 fields) was used to standardize the optical analysis. Material loss due to mechanical stress compared to CG (score 0.00) was CP (1.2%), FP (21.5%), LB (22.2%) and PN (81.1%). No significant difference to CG presented PS. Material loss due to thermal stress was CP (0.5%), PS (2%), FP (2.6%), LB (3.1%) and PN (39.9%). Material loss due to chemical stress was FP (1.8%), PS (2.1%), LB (5.5%) and PN (39.6%). No significant difference to CG presented CP. Only PS and CP had optically provable, good resiliance to mechanical, thermal and chemical stress. Significantly poorer outcomes in particular showed PN.

Background: Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha-fetoprotein (AFP) is a well-established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion., Objective: We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort., Methods: Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg University Mainz between 1998 and 2014 and two available pretreatment AFP-values (AFP-slope) were retrospectively analysed. Clinicopathological baseline parameters, pretreatment static values and AFP-slope were assessed. Prognostic impact was determined by Kaplan-Meier analyses and Cox regression models., Results: High static and dynamic AFP variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child-Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic AFP variable resulted in higher time-dependent area under the curves. Notably, in patients with more favourable prognosis, AFP-slope prior to therapy was a slightly stronger predictor for overall survival compared with static AFP values., Conclusion: Static and dynamic AFP variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP-slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: The perioperative surgical home is a patient-centered, team-based model of care developed in the USA to coordinate diagnosis, treatment and follow-up; however, due to different healthcare systems, scientific findings in the USA cannot be simply transferred to Germany., Objective: This preliminary study was carried out to evaluate the effects of a new interdisciplinary treatment bundle (patient-centered perioperative vigilance, PPV) in a German university hospital., Material and Methods: After IRB approval and written informed consent, 34 patients (PPV group) undergoing elective endoprosthetic surgery were enrolled after introduction of the PPV bundle (1. preoperative patient education, 2. specific surgical technique, 3. specific anesthesia technique, 4. start of mobilization on day of operation) and compared to historic matched pairs (HMP) for age cohort, ASA-PS, body mass index, and sex. We hypothesized that PPV shortens induction time (primary outcome). Secondary outcomes were length of hospital stay (LOS), resting pain and pain with movement on postoperative day 1 and mobilization progress on postoperative days 1, 3 and 6. Groups were compared with Wilcoxon-Mann-Whitney test for noninferiority. In the case of noninferiority, a Wilcoxon-Whitney-Mann test for superiority was additionally applied., Results: The median anesthesia induction time was 13.5 min for PPV and 60 min for HMP (p < 0.0001). The LOS was 8 days for PPV and 12 days for HMP (p < 0.0001). Resting pain on postoperative day 1 was 20 for PPV (30 for HMP). Pain with movement was identical (median 40). Mobilization progress was better for PPV on days 1, 3 and 6 (p < 0.0001 for each day)., Conclusion: The concept of patient-centered perioperative vigilance (PPV) shortens induction time and hospital length of stay. Mobilization improves with PPV on day 1. Higher pain scores in PPV seem to be clinically insignificant, which warrants further study.

Background: Pain is a devastating sensation and has to be treated immediately. Therefore, we developed a training program to improve the knowledge of medical students in the field of pain medicine. In the present study, the applicability and efficacy of this training program was tested., Methods: Half of the students attended first a training with simulated patients (SP) followed by bedside teaching (Group 1). Group 2 performed the training programs in reverse order. The evaluation based on standardized questionnaires completed by students (self-assessment) and all students took part in two practical examinations after the learning interventions., Results: This study included 35 students. The quality of the simulation was evaluated by the students with average grade 1.1 (1 = very good, 6 = very bad). The practical work on the ward with patients was rated with grade 1.4 of 6, the whole course with 1.1. Students of Group A were significantly better in the final examination (grade 1.7 vs. grade 2.2, p < 0.05). To rate the improvement of skills (self-assessment) we used a Likert Scale (1 = very certain, 5 = very uncertain). The following skills were similar in both groups and significantly better after the course: taking responsibility, expert knowledge, empathy, relationship building and communication., Conclusions: Training with simulated patients in combination with small-group teaching at the bedside with real patients achieves a dramatic increase in student competence. Students prefer learning from the simulation before bedside teaching and propose to include simulation into the curricular teaching of pain medicine.

Introduction: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes., Methods: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism., Results: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001)., Conclusions: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups., Competing Interests: Conflict of interest: S. Barco reports personal fees from Biocompatibles Group UK, LEO Pharma, Bayer, nonfinancial support from Bayer HealthCare and Daiichi Sankyo, grants from Sanofi, outside the submitted work. Conflict of interest: I. Schmidtmann reports grants from Merck Serono, outside the submitted work. Conflict of interest: W. Ageno reports grants from Bayer, personal fees from Boehringer Ingelheim, Daiichi Sankyo and Bristol Myers Squibb/Pfizer, outside the submitted work. Conflict of interest: T. Anušić has nothing to disclose. Conflict of interest: R.M. Bauersachs reports personal fees for lectures and advisory board work from Bayer HealthCare, Bristol Myers Squibb/Pfizer and Daiichi Sankyo, during the conduct of the study. Conflict of interest: C. Becattini reports personal fees for consultancy and lectures from Bayer HealthCare, Daiichi Sankyo and Bristol Myers Squibb, outside the submitted work. Conflict of interest: E. Bernardi has nothing to disclose. Conflict of interest: J. Beyer-Westendorf reports patient fees from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; grants and personal fees for advisory board work, lectures and travel support from Bayer, outside the submitted work. Conflict of interest: L. Bonacchini has nothing to disclose. Conflict of interest: J. Brachmann reports grants and personal fees from Medtronic, during the conduct of the study; grants from Medtronic, St Jude and Biotronik, outside the submitted work. Conflict of interest: M. Christ reports grants from the University of Mainz, during the conduct of the study. Conflict of interest: M. Czihal reports personal fees from Bayer HealthCare, Roche, AstraZeneca, MSD Sharp & Dohme and LEO Pharma, outside the submitted work. Conflict of interest: D. Duerschmied reports personal fees for lectures and nonfinancial support (travel costs) from Bayer, Pfizer, Daiichi Sankyo and CytoSorbents, outside the submitted work. Conflict of interest: K. Empen reports travel costs and personal fees for lectures from Bayer HealthCare, outside the submitted work. Conflict of interest: C. Espinola-Klein reports lecture fees from Bayer HealthCare, outside the submitted work. Conflict of interest: J.H. Ficker reports personal fees for lectures from Daiichi Sankyo, outside the submitted work. Conflict of interest: C. Fonseca reports personal fees for consultancy and lectures from Bayer, outside the submitted work Conflict of interest: S. Genth-Zotz has nothing to disclose. Conflict of interest: D. Jiménez has nothing to disclose. Conflict of interest: V-P. Harjola reports personal fees for lectures from Bayer, personal fees for lectures and advisory board work from Boehringer Ingelheim and Pfizer, personal fees for advisory board work from MSD, outside the submitted work. Conflict of interest: M. Held reports honoraria for advisory board work from Actelion, Bayer, Boehringer, MSD, Daiichi Sankyo and Roche, honoraria for lectures from Actelion, Bayer, Berlin-Chemie, Bristol Myers Squibb, MSD, Daichi Sankyo, Pfizer and OMT, grants from Actelion, outside the submitted work. Conflict of interest: L. Iogna Prat has nothing to disclose. Conflict of interest: T.J. Lange reports nonfinancial support for meeting attendance from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; personal fees from Bayer and Pfizer, outside the submitted work. Conflict of interest: M. Lankeit reports personal fees for lectures and nonfinancial support (travel costs) from Actelion, Bayer and Daiichi Sankyo, personal fees for lectures from MSD and Bristol Myers Squibb/Pfizer, grants from BRAHMS – Thermo Fisher Scientific, outside the submitted work. Conflict of interest: A. Manolis has nothing to disclose. Conflict of interest: A. Meyer has nothing to disclose. Conflict of interest: T. Münzel has nothing to disclose. Conflict of interest: P. Mustonen reports personal fees for lectures and advisory board work from Boehringer Ingelheim, Bayer, Sanofi-Anetis, LEO Pharma, Bristol Myers Squibb/Pfizer and MSD, outside the submitted work. Conflict of interest: U. Rauch-Kroehnert reports grants from Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Interdisziplinäres Zentrum Klinische Studien (IZKS) during the conduct of the study; personal fees from Bayer Vital, outside the submitted work. Conflict of interest: P. Ruiz-Artacho reports personal fees from Bayer, Daiichi Sankyo, Sanofi, Pfizer, LEO Pharma and Rovi, outside the submitted work. Conflict of interest: S. Schellong reports personal fees for lectures and consultancy from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Aspen, grants and personal fees for lectures and consultancy from Bristol Myers Squibb, outside the submitted work. Conflict of interest: M. Schwaiblmair has nothing to disclose. Conflict of interest: R. Stahrenberg has nothing to disclose. Conflict of interest: L. Valerio has nothing to disclose. Conflict of interest: P.E. Westerweel has nothing to disclose. Conflict of interest: P.S. Wild reports grants and personal fees from Boehringer Ingelheim, Sanofi-Aventis, Bayer Vital and Bayer HealthCare, grants from Philips Medical Systems and Daiichi Sankyo Europe, personal fees from AstraZeneca, personal fees and equipment provision from DiaSorin, equipment provision from IEM, outside the submitted work. Conflict of interest: S.V. Konstantinides reports grants and provision of study drug from Bayer, during the conduct of the study; grants and personal fees for consultancy and lectures from Boehringer Ingelheim, Daiichi Sankyo, Biocompatibles Group UK and MSD, personal fees for consultancy and lectures from Bayer and Bristol Myers Squibb/Pfizer, grants and personal fees for lectures from Actelion, grants from Servier, outside the submitted work., (Copyright ©ERS 2021.)

Background Vascular alterations induced by antineoplastic treatment might be considered as a possible underlying mechanism of increased cardiovascular sequelae in childhood cancer survivors (CCSs). We aimed to evaluate arterial stiffness among long-term CCSs and to compare the data against a population-based sample. Methods and Results Arterial stiffness was assessed by digital photoplethysmography (stiffness index; m/s) among 1002 participants of the CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study, diagnosed with neoplasia (1980-1990) before an age of 15 years. A population-based sample from the GHS (Gutenberg Health Study) (n=5252) was investigated for comparison. All subjects underwent a comprehensive, standardized clinical examination in the same study center. CCSs had higher stiffness index (β=0.66 m/s; 95% CI, 0.51-0.80 m/s) in multivariable linear regression analysis after adjustment for cardiovascular risk factors compared with the population sample of comparable age range. Stiffer vessels were found among CCSs also in absence of arterial hypertension (β=0.66; 95% CI, 0.50-0.81) or history of chemotherapy/radiotherapy (β=0.56; 95% CI, 0.16-0.96) in fully adjusted models. Moreover, stiffness index differed by tumor entity, with highest values in bone and renal tumors. Almost 5.2-fold higher prevalence of stiffness index values exceeding age-specific, population-based reference limits was observed among CCSs compared with GHS participants. Conclusions This is the first study demonstrating increased arterial stiffness among long-term CCSs. The data suggest that vascular compliance might differ in survivors of childhood cancer from the established development concept for arterial stiffness in the population; cancer growth and antineoplastic treatment might be relevant determinants of the pathobiological features. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02181049.

Objective:  Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality., Methods:  Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study ( n  = 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality., Results:  Multivariable linear regression analysis identified smoking ( β 0.095 [0.054-0.136]) as a positive determinant for total TFPI activity, while diabetes ( β -0.072 [-0.134 to -0.009]), obesity ( β -0.063 [-0.101 to -0.024]), and history of coronary artery disease (CAD) were negatively associated with total TFPI activity, independent of age, sex, and the remaining cardiovascular risk factors. After adjustment for lipoprotein levels, the association between total TFPI activity levels and obesity and CAD was lost. The analysis additionally revealed a strong positive association between total TFPI activity levels and low-density lipoprotein ( β 0.221 [0.204-0.237]). The Cox regression models revealed that a higher total TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (hazard ratio = 2.58 [95% confidence interval: 1.49-4.47]), independent of age, sex, and cardiovascular risk profile., Conclusion:  In the Gutenberg Health Study population-based cohort, the highest percentage of total TFPI correlated with an increased mortality risk. While elevated TFPI may reflect endothelial cell activation, the associations between total TFPI activity and obesity and CAD, points to additional mechanistic interactions., Competing Interests: None declared., (Thieme. All rights reserved.)