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Parkinson's disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson's patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins-Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson's disease., (© 2024. The Author(s).)

Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson's disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-naïve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials., (© 2024. The Author(s).)

We tested the potential for recommender system technology to provide personalized physical activity (PA) suggestions for inactive young adults with high bodyweight. We developed a recommender system using data from the 2017 Behavioral Risk Factor Surveillance System and assessed interest in using the system among 47 young adults (mean age = 23.0 years; 63.4% female; 65.0% White; mean BMI = 29.4). Eleven of these participants (mean age = 23.6 years; 90.9% female, 63.6% White; average BMI = 28.5) also received a PA recommendation and a follow-up interview. Approximately half of the survey participants were willing to use the recommender system, and participants interested in the recommender system differed from those unwilling to try the system (e.g., more likely to be female, worse self-perceived health). Furthermore, eight of the 11 interviewees tried the PA recommended to them, but had mixed reviews of the system's accuracy. Although our recommender system requires improvements, such systems have promise for supporting PA adoption., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Chronic inflammatory diseases like rheumatoid arthritis (RA) and neurodegenerative disorders like Parkinson's disease (PD) have recently been associated with a decreased diversity in the gut microbiome, emerging as key driver of various diseases. The specific interactions between gut-borne microorganisms and host pathophysiology remain largely unclear. The microbiome can be modulated by interventions comprising nutrition.The aim of our clinical study is to (1) examine effects of prolonged fasting (PF) and time-restricted eating (TRE) on the outcome parameters and the immunophenotypes of RA and PD with (2) special consideration of microbial taxa and molecules associated with changes expected in (1), and (3) identify factors impacting the disease course and treatment by in-depth screening of microorganisms and molecules in personalised HuMiX gut-on-chip models, to identify novel targets for anti-inflammatory therapy., Methods and Analysis: This trial is an open-label, multicentre, controlled clinical trial consisting of a cross-sectional and a longitudinal study. A total of 180 patients is recruited. For the cross-sectional study, 60 patients with PD, 60 patients with RA and 60 healthy controls are recruited at two different, specialised clinical sites. For the longitudinal part, 30 patients with PD and 30 patients with RA undergo 5-7 days of PF followed by TRE (16:8) for a period of 12 months. One baseline visit takes place before the PF intervention and 10 follow-up visits will follow over a period of 12 months (April 2021 to November 2023)., Ethics and Dissemination: Ethical approval was obtained to plan and conduct the trial from the institutional review board of the Charité-Universitätsmedizin Berlin (EA1/204/19), the ethics committee of the state medical association (Landesärztekammer) of Hessen (2021-2230-zvBO) and the Ethics Review Panel (ERP) of the University of Luxembourg (ERP 21-001 A ExpoBiome). The results of this study will be disseminated through peer-reviewed publications, scientific presentations and social media., Trial Registration Number: NCT04847011., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed., Objectives: To update LED conversion formulae based on a systematic review., Methods: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency., Results: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon., Conclusions: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD)., Objectives: The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline., Methods: We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales., Results: αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression., Conclusions: Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Recent studies point toward a significant impact of cardiovascular processes and inflammation on Parkinson's disease (PD) progression., Objective: The aim of this study was to assess established markers of neuronal function, inflammation, and cardiovascular risk by high-throughput sandwich immune multiplex panels in deeply phenotyped PD., Methods: Proximity Extension Assay technology on 273 markers was applied in plasma of 109 drug-naive at baseline (BL) patients with PD (BL, 2-, 4-, and 6-year follow-up [FU]) and 96 healthy control patients (HCs; 2- and 4-year FU) from the de novo Parkinson's cohort. BL plasma from 74 individuals (37 patients with PD, 37 healthy control patients) on the same platform from the Parkinson Progression Marker Initiative was used for independent validation. Correlation analysis of the identified markers and 6 years of clinical FU, including motor and cognitive progression, was evaluated., Results: At BL, 35 plasma markers were differentially expressed in PD, showing downregulation of atherosclerotic risk markers, eg, E-selectin and ß 2 -integrin. In contrast, we found a reduction of markers of the plasminogen activation system, eg, urokinase plasminogen activator. Neurospecific markers indicated increased levels of peripheral proteins of neurodegeneration and inflammation, such as fibroblast growth factor 21 and peptidase inhibitor 3. Several markers, including interleukin-6 and cystatin B, correlated with cognitive decline and progression of motor symptoms during FU. These findings were independently validated in the Parkinson Progression Marker Initiative., Conclusions: We identified and validated possible PD plasma biomarker candidates for state, fate, and disease progression, elucidating new molecular processes with reduced endothelial/atherosclerotic processes, increased thromboembolic risk, and neuroinflammation. Further investigations and validation in independent and larger longitudinal cohorts are needed. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: The aim of this study was to develop an algorithm that corrects the image of an electronic portal imaging device (EPID) of a linear accelerator so that it can be used for dosimetric purposes, such as in vivo dosimetry or quality assurance for photon radiotherapy. For that purpose, the impact of the field size, phantom thickness, and the varying spectral photon distribution within the irradiation field on the EPID image was investigated., Methods: The EPID measurements were verified using reference measurements with ionization chambers. Therefore, absolute dose measurements with an ionization chamber and relative dose measurements with a detector array were performed. An EPID calibration and correction algorithm was developed to convert the EPID image to a dose distribution. The algorithm was validated by irradiating inhomogeneous phantoms using square fields as well as irregular IMRT fields., Results: It was possible to correct the influence of the field size, phantom thickness on the EPID signal as well as the homogenization of the image profile by several correction factors within 0.6%. A gamma index analysis (3%, 3 mm) of IMRT fields showed a pass rate of above 99%, when comparing to the planning system., Conclusion: The developed algorithm enables an online dose measurement with the EPID during the radiation treatment. The algorithm is characterized by a robust, non-iterative, and thus real-time capable procedure with little measuring effort and does not depend on system-specific parameters. The EPID image is corrected by multiplying three independent correction factors. Therefore, it can easily be extent by further correction factors for other influencing variables, so it can be transferred to other linear accelerators and EPID configurations., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

The presence of neutralizing antibodies against SARS-CoV-2 correlates with protection against infection and severe COVID-19 disease courses. Understanding the dynamics of antibody development against the SARS-CoV-2 virus is important for recommendations on vaccination strategies and on control of the COVID-19 pandemic. This study investigates the dynamics and extent of α-Spike-Ab development by different vaccines manufactured by Johnson & Johnson, AstraZeneca, Pfizer-BioNTech and Moderna. On day 1 after vaccination, we observed a temporal low-grade inflammatory response. α-Spike-Ab titers were reduced after six months of vaccination with mRNA vaccines and increased 14 days after booster vaccinations to a maximum that exceeded titers from mild and critical COVID-19 and Long-COVID patients. Within the group of critical COVID-19 patients, we observed a trend for lower α-Spike-Ab titers in the group of patients who survived COVID-19. This trend accompanied higher numbers of pro-B cells, fewer mature B cells and a higher frequency of T follicular helper cells. Finally, we present data demonstrating that past infection with mild COVID-19 does not lead to long-term increased Ab titers and that even the group of previously infected SARS-CoV-2 patients benefit from a vaccination six months after the infection.

Competing Interests: The 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.

Interrogation is a core task of practical police work. The outcomes of interrogation often provide crucial evidence for solving criminal cases. The success of interrogation depends on interactions between police officers and citizens. Based on a comprehensive literature overview, we propose a three-factor typology for interrogations by police officers. First, the competencies of police officers refer to the application of personal, professional, social, and methodological capabilities. The underlying concept of interrogation refers to the application of both explicit and implicit experience-based interrogation models. Communication refers to the goal-directed application of communication tactics and techniques. According to this typology, we discuss the major objectives of police interrogation in police service and training from police officers' perspectives. The present study provides guidance for practical police services and training by offering an evidence-based interrogation standard., Competing Interests: The 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 Thielgen, Schade and Niegisch.)

Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress., (© 2022. The Author(s).)

Background: The MDS-Unified Parkinson's disease (PD) Rating Scale (MDS-UPDRS) is the most used scale in clinical trials. Little is known about the predictive potential of its single items., Objective: To systematically dissect MDS-UPDRS to predict PD progression., Methods: 574 de novo PD patients and 305 healthy controls were investigated at baseline (BL) in the single-center DeNoPa (6-year follow-up) and multi-center PPMI (8-year follow-up) cohorts. We calculated cumulative link mixed models of single MDS-UPDRS items for odds ratios (OR) for class change within the scale. Models were adjusted for age, sex, time, and levodopa equivalent daily dose. Annual change and progression of the square roots of the MDS-UDPRS subscores and Total Score were estimated by linear mixed modeling., Results: Baseline demographics revealed more common tremor dominant subtype in DeNoPa and postural instability and gait disorders-subtype and multiethnicity in PPMI. Subscore progression estimates were higher in PPMI but showed similar slopes and progression in both cohorts. Increased ORs for faster progression were found from BL subscores I and II (activities of daily living; ADL) most marked for subscore III (rigidity of neck/lower extremities, agility of the legs, gait, hands, and global spontaneity of movements). Tremor items showed low ORs/negative values., Conclusion: Higher scores at baseline for ADL, freezing, and rigidity were predictors of faster deterioration in both cohorts. Precision and predictability of the MDS-UPDRS were higher in the single-center setting, indicating the need for rigorous training and/or video documentation to improve its use in multi-center cohorts, for example, clinical trials.

Background: Objective diagnostic biomarkers are needed to support a clinical diagnosis., Objectives: To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF)., Methods: Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker., Results: CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P < 0.05). As expected, some of the markers were highest in AD (i.e., UCHL-1, GFAP, S100B, sTREM-2, YKL-40). Within ASRD, CSF NfL levels were higher in MSA than PD and DLB (P < 0.05). Comparing PD to HC, interesting serum markers were S100B (AUC: 0.86), sTREM2 (AUC: 0.87), and NfL (AUC: 0.78). CSF S100B and serum GFAP were highest in DLB., Conclusions: Levels of most marker candidates tested in serum and CSF significantly differed between disease groups and HC. In the stratification of PD versus other tau- or aSyn-related conditions, CSF NfL levels best discriminated PD and MSA. CSF S100B and serum GFAP best discriminated PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

In the present study, we investigated whether police officers' performance in searching for unfamiliar faces in a video-based real-world task is predicted by laboratory-based face processing tests that are typically used to assess individual differences in face processing abilities. Specifically, perceptual performance in the field was operationalized via the identification of target individuals in self-made close-circuit television (CCTV) video tapes. Police officers' abilities in the laboratory were measured by the Cambridge Face Memory Test long form (CFMT+). We hypothesized that the CFMT+ predicts individual differences in the CCTV task performance. A total of N = 186 police officers of the Rhineland-Palatinate State Police participated in the study (i.e., N = 139 novice and advanced cadets with either 3 months, 15 months or 24 months of pre-service experience; N = 47 experienced police officers with three years of pre-service experience and at least two years of full-service experience, who participated in the assessment center of the special police forces, specifically the surveillance and technical unit). Results revealed that the CFMT+ explained variance in the CCTV task. In sample 1, CFMT+ scores predicted hits, but not false alarms. In contrast, in sample 2, CFMT+ scores were correlated with both hits and false alarms. From a theoretical perspective, we discuss factors that might explain CCTV task performance. From a practical perspective, we recommend that personnel selection processes investigating individual differences of police officers' face processing abilities should comprise of two steps. At first, laboratory-based tests of face processing abilities should be applied. Subsequently, to validate laboratory-based individual differences in face processing abilities, we recommend that work samples such as CCTV tasks from the field should be added., (© 2021. The Author(s).)

Purpose: Postoperative pulmonary embolism (PE) after pancreatic surgery is a potentially life-threatening complication. However, the magnitude of morbidity and mortality of PE is still uncertain. The present study aims to assess the incidence of PE after pancreatic surgery and analyze its impact on the outcome., Methods: We conducted a retrospective study including all patients who underwent pancreatic resections between 2005 and 2017. The development of PE was analyzed for a 90-day period following surgery. Risk factors were evaluated using regression models., Results: The study investigated 947 patients undergoing pancreatic surgery. Overall, 26 (2.7%) patients developed PE. The median body mass index (BMI) of patients with PE was significantly higher (28.1 kg/m 2 [24.7-31.8] vs. 24.8 kg/m 2 [22.4-27.8], p < 0.001). Patients with PE had a significantly increased duration of the operation and more often underwent multivisceral resections. The lowest incidence of PE was found after distal or total pancreatectomy (2%). In median, PE occurred on the fifth postoperative day (interquartile range: 3-9). Increased BMI, duration of operation, and postoperative deep venous thrombosis were found to be multivariate risk factors for the development of PE. Importantly, postoperative complications (53.8% vs. 15.1%, p < 0.001) and the 30-day mortality rate were significantly increased in the PE group (19.2% vs. 3.3%, p < 0.001)., Conclusions: Patients with increased BMI, a history of deep venous thrombosis, and multivisceral resections are a high-risk group for PE after pancreatic surgery. While the absolute incidence and related mortality of PE after pancreatic surgery is low, it is associated with severe sequelae.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker., Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers., Results: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association., Conclusions: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

： Objectives : A postoperative pancreatic fistula (POPF) is defined as a threefold increase in the amylase concentration in abdominal drains on or after the third postoperative day (POD). However, additional lipase fluid analysis is widely used despite lacking evidence. In this study, drain amylase and lipase levels were compared regarding their value in detecting POPF. Methods: 990 patients were included in the analysis. Overall, 333 (34%) patients developed a POPF. The median amylase and lipase concentrations at POD 3 in cases with POPF were 11.55 µmol/(s·L) (≈13 ×-fold increase) and 39 µmol/(s·L) (≈39 ×-fold increase), respectively. Seven patients with subsequent POPF (2%) were missed with amylase analysis on POD 3, but detected using 3-fold lipase analysis. The false-positive rate of lipase was 51/424 = 12%. A cutoff lipase value at POD 3 of > 4.88 yielded a specificity of 94% and a sensitivity of 89% for development of a POPF. Increased body mass index turned out as risk factor for the development of POPF in a multivariable model. Results: 990 patients were included in the analysis. Overall, 333 (34%) patients developed a POPF. The median amylase and lipase concentrations at POD 3 in cases with POPF were 11.55 µmol/(s·L) (≈13 ×-fold increase) and 39 µmol/(s·L) (≈39 ×-fold increase), respectively. Seven patients with subsequent POPF (2%) were missed with amylase analysis on POD 3, but detected using 3-fold lipase analysis. The false-positive rate of lipase was 51/424 = 12%. A cutoff lipase value at POD 3 of > 4.88 yielded a specificity of 94% and a sensitivity of 89% for development of a POPF. Increased body mass index turned out as risk factor for the development of POPF in a multivariable model. Conclusions : Threefold-elevated lipase concentration may be used as an indicator of a POPF. However, the additional detection of POPF using simultaneous lipase analysis is marginal. Therefore, assessment of lipase concentration does not provide added clinical value and only results in extra costs., Competing Interests: The authors declare that they have no conflicts of interest.

Some species responded successfully to prehistoric changes in climate [1, 2], while others failed to adapt and became extinct [3]. The factors that determine successful climate adaptation remain poorly understood. We constructed a reference genome and studied physiological adaptations in the Alpine marmot (Marmota marmota), a large ground-dwelling squirrel exquisitely adapted to the "ice-age" climate of the Pleistocene steppe [4, 5]. Since the disappearance of this habitat, the rodent persists in large numbers in the high-altitude Alpine meadow [6, 7]. Genome and metabolome showed evidence of adaptation consistent with cold climate, affecting white adipose tissue. Conversely, however, we found that the Alpine marmot has levels of genetic variation that are among the lowest for mammals, such that deleterious mutations are less effectively purged. Our data rule out typical explanations for low diversity, such as high levels of consanguineous mating, or a very recent bottleneck. Instead, ancient demographic reconstruction revealed that genetic diversity was lost during the climate shifts of the Pleistocene and has not recovered, despite the current high population size. We attribute this slow recovery to the marmot's adaptive life history. The case of the Alpine marmot reveals a complicated relationship between climatic changes, genetic diversity, and conservation status. It shows that species of extremely low genetic diversity can be very successful and persist over thousands of years, but also that climate-adapted life history can trap a species in a persistent state of low genetic diversity., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The 5-HT 7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT 7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K i 5-HT7 R  = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C max  = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT 7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Algae are key components of aquatic food chains. Consequently, they are internationally recognised test species for the environmental safety assessment of chemicals. However, existing algal toxicity test guidelines are not yet optimized to discover molecular modes of action, which require highly-replicated and carefully controlled experiments. Here, we set out to develop a robust, miniaturised and scalable Chlamydomonas reinhardtii toxicity testing approach tailored to meet these demands. We primarily investigated the benefits of synchronised cultures for molecular studies, and of exposure designs that restrict chemical volatilisation yet yield sufficient algal biomass for omics analyses. Flow cytometry and direct-infusion mass spectrometry metabolomics revealed significant and time-resolved changes in sample composition of synchronised cultures. Synchronised cultures in sealed glass vials achieved adequate growth rates at previously unachievably-high inoculation cell densities, with minimal pH drift and negligible chemical loss over 24-h exposures. Algal exposures to a volatile test compound (chlorobenzene) yielded relatively high reproducibility of metabolic phenotypes over experimental repeats. This experimental test system extends existing toxicity testing formats to allow highly-replicated, omics -driven, mode-of-action discovery.

Background: Laparoscopic adjustable gastric banding has been the gold standard for surgical management of obesity over the last decades in USA and Europe. However, significant complications have been documented due to foreign body placement, including band erosions. Our treatment approach for erosions is rather observant with regular follow-up until the band has sufficiently perforated the gastric wall which facilitates endoscopic removal. Consequences of a not followed-up band erosion may present even after a long time following initial diagnosis with more severe complications., Case Presentation: A 51-year-old Caucasian woman presented to our out-patients' clinic with a 2-week history of worsening abdominal pain in her left upper quadrant, exacerbated by abdominal flexion and extension maneuvers. Here we describe a case involving gastric penetration and subsequent downward migration of a band into distal jejunum causing small bowel obstruction, which occurred more than 10 years following initial diagnosis of erosion. The perforation was missed due to cessation of endoscopic follow-up., Conclusion: Prospective and long-term follow-up is mandatory in those with partial band erosion to avoid further complications.

In highly complex task situations (dual tasking), stressed individuals have been shown to adapt the most resource-efficient task processing strategy, accepting costs of performance. We argue that an interpretation of this behavior in terms of a stress-induced impairment of cognitive control might be too simplified. In the present study, we therefore tested whether stressed individuals are still capable to up-regulate cognitive control when instructed to adapt more resource-intensive strategies, enabling preservation of task performance. Fifty-six participants underwent either an established psychosocial stress induction protocol (Trier Social Stress Test) or a standardized control intervention. Afterwards, all participants performed a dual task in which task prioritization was systematically varied, calling for the adoption of different task processing strategies that require more or less voluntary top-down control. Although individuals of the stress group showed a pronounced stress response, as indicated by salivary cortisol, they were able to recruit more resources and to engage more voluntary top-down control when instructed to do so. This finding suggests an adaptive nature of control regulation under acute stress that reflects a compensatory capacity with the potential to account for some of the observed ostensible impairments of cognitive control. Our finding calls for careful empirical examination of whether stressed individuals cannot or do not recruit certain cognitive control functions in a given situation that will inform novel interventions to optimize performance in high-stress environments., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The precise clinical diagnosis of Parkinson's disease (PD) can be difficult in the early stages. Diagnostic criteria include the response of key motor features to levodopa as a supportive prospective criterion. Data are sparse on the diagnostic value of the acute levodopa challenge test (LDCT) in patients with de novo PD. The objective of this study was to validate the LDCT as a tool in the early clinical diagnosis of PD., Methods: We performed the standardized LDCT with 250 mg levodopa in the prospective longitudinal cohort study "DeNoPa," comprising 159 patients with de novo PD, and carried out longitudinal clinical follow-up for 24 months. Motor assessments at baseline using the motor part (part III) of the Unified Parkinson's Disease Rating Scale before and 1 hr after drug administration were documented. The optimal cutoff score on the LDCT was calculated using the Youden index., Results: Clinical reassessment of 144 patients who returned for follow-up confirmed the diagnosis of PD in 120 patients (83%). In 24 patients (17%), the initial diagnoses were revised and classified as other neurologic disorders. The optimal cutoff at 33% improvement of motor symptoms on the part 3 of the Unified Parkinson's Disease Rating Scale during the LDCT reached a sensitivity of 70% a specificity of 71%. The positive and negative predictive values were 92% and 32%, respectively. Sensitivity (91%), specificity (79%), and positive/negative (96%/63%) predictive values improved with the addition of further clinical information (urinary incontinence, fainting, asymmetric tremor, and amount of further drug-intake)., Conclusions: The LDCT is a reliable tool in the early diagnosis of PD. The accuracy of this test can be further improved by additional, easy-to-acquire clinical information provided by patients. © 2017 International Parkinson and Movement Disorder Society.

Predicting oral bioavailability (F oral ) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human F oral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery., (Copyright © 2016 Elsevier B.V. All rights reserved.)

D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer's disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

The widespread diffusion of sensors, mobile devices, social media and open data are reconfiguring the way data underpinning policy and science are being produced and consumed. This in turn is creating both opportunities and challenges for policy-making and science. There can be major benefits from the deployment of the IoT in smart cities and environmental monitoring, but to realize such benefits, and reduce potential risks, there is an urgent need to address current limitations, including the interoperability of sensors, data quality, security of access and new methods for spatio-temporal analysis. Within this context, the manuscript provides an overview of the AirSensEUR project, which establishes an affordable open software/hardware multi-sensor platform, which is nonetheless able to monitor air pollution at low concentration levels. AirSensEUR is described from the perspective of interoperable data management with emphasis on possible use case scenarios, where reliable and timely air quality data would be essential.

Recent technological advancements have led to the production of arrays of miniaturized sensors, often embedded in existing multitasking devices (e.g., smartphones, tablets) and using a wide range of radio standards (e.g., Bluetooth, Wi-Fi, 4G cellular networks). Altogether, these technological evolutions coupled with the diffusion of ubiquitous Internet connectivity provide the base-line technology for the Internet of Things (IoT). The rapid increase of IoT devices is enabling the definition of new paradigms of data collection and introduces the concept of mobile crowd-sensing. In this respect, new sensing methodologies promise to extend the current understanding of the environment and social behaviors by leveraging citizen-contributed data for a wide range of applications. Environmental sensing can however only be successful if all the heterogeneous technologies and infrastructures work smoothly together. As a result, the interconnection and orchestration of devices is one of the central issues of the IoT paradigm. With this in mind, we propose an approach for improving the accessibility of observation data, based on interoperable standards and on-device web services.

Dementia with Lewy bodies (DLB) has become the second most common neurodegenerative dementia due to demographic ageing. Differential diagnosis is still troublesome especially in early stages of the disease, since there is a great clinical and neuropathological overlap primarily with Alzheimer's disease and Parkinson's disease. Therefore, more specific biomarkers, not only for scientific reasons but also for clinical therapeutic decision-making, are urgently needed. In this review, we summarize the knowledge on fluid biomarkers for DLB, derived predominantly from cerebrospinal fluid. We discuss the value of well-defined markers (β-amyloid, (phosphorylated) tau, α-synuclein) as well as some promising 'upcoming' substances, which still have to be further evaluated.

The transcription factors hypoxia-inducible factor-1 and -2 (HIF-1 and HIF-2) orchestrate a multitude of processes that allow tumor cells to survive under conditions of low oxygen and nutrients, and that lead to resistance to some apoptotic pathways and facilitate invasion and metastasis. Therefore, inhibition of transactivation by HIF has become an attractive target in cancer research. Herein we present the results of a cell-based screening approach that led to the discovery of substituted 1H-pyrazole-3-carboxamides. Chemical optimization of the hit class with respect to potency and metabolic stability is described; it resulted in novel 5-(1H-pyrazol-3-yl)-1,2,4-oxadiazoles that inhibit the hypoxia-induced accumulation of HIF-1α and HIF-2α. The HIF inhibitory potency in the screening cell system was improved from IC₅₀ 190 to 0.7 nM, and significant parts of the SAR are disclosed. For a key compound, the ability to suppress the hypoxia-induced expression of HIF target genes was studied in A549 human lung adenocarcinoma cells. The same compound shows a favorable pharmacokinetic profile in rats after i.v. and p.o. administration., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Centrosome morphology and number are frequently deregulated in cancer cells. Here, to identify factors that are functionally relevant for centrosome abnormalities in cancer cells, we established a protein-interaction network around 23 centrosomal and cell-cycle regulatory proteins, selecting the interacting proteins that are deregulated in cancer for further studies. One of these components, LGALS3BP, is a centriole- and basal body-associated protein with a dual role, triggering centrosome hypertrophy when overexpressed and causing accumulation of centriolar substructures when downregulated. The cancer cell line SK-BR-3 that overexpresses LGALS3BP exhibits hypertrophic centrosomes, whereas in seminoma tissues with low expression of LGALS3BP, supernumerary centriole-like structures are present. Centrosome hypertrophy is reversed by depleting LGALS3BP in cells endogenously overexpressing this protein, supporting a direct role in centrosome aberration. We propose that LGALS3BP suppresses assembly of centriolar substructures, and when depleted, causes accumulation of centriolar complexes comprising CPAP, acetylated tubulin and centrin.

Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.

A major control demand in successful dual-task performance is the task-specific separation of task-goal representations and of the related stimulus-response translation processes. In the present study, we investigated how these cognitive control processes of task shielding are affected by acute psychosocial stress. Fifty-six healthy participants were exposed to either an acute psychosocial stressor (the Trier Social Stress Test) or a standardized control situation prior to a dual task. Task shielding was assessed by analyzing the interference of Task 2 processing on prioritized Task 1 performance. Following successful stress induction, as indicated by increases in salivary α-amylase (sAA) and cortisol that reflect increases in sympathetic nervous system and hypothalamus-pituitary-adrenal (HPA) axis activity, respectively, stressed individuals displayed reduced task shielding relative to controls. This result was further substantiated by a correlation between treatment-related increase in cortisol, but not sAA, and between-task interference, suggesting a potential role of the HPA stress response for the development of the observed effects. As an additional finding, when the volunteers were categorized with regard to their action-state orientation, their orientation did not interact with stress but did reveal generally increased between-task interference, and thus inferior task shielding, for state-oriented as compared to action-oriented individuals.

Purpose: Transcranial direct current stimulation (tDCS) has proven to be a useful tool for fundamental brain research as well as for attempts in therapy of neurological and psychiatric diseases by modulating neuronal plasticity. Little is understood about the effects of tDCS are influenced by hemispheric dominance, even less in terms of handedness. The aim of our pilot study was to investigate whether tDCS induced neuroplastic changes may be different in right- and left-handed individuals due to existing differences in hemispheric lateralisation., Methods: We measured changes in motor evoked potentials (MEPs) after application of tDCS in 8 right-handers, 8 left-handers and 8 mixed-handers according to the Edinburgh Handedness Inventory (EHI). In double-blind sessions, we applied either anodal or cathodal tDCS for 5 minutes for each hemisphere., Results: While motor thresholds (MT) seem to be not influenced by handedness significantly, in right-handed subjects we reproduced the well-known effects of tDCS: anodal stimulation increased while cathodal stimulation decreased MEP amplitudes. However, left-and mixed-handed subjects differed from right-handed subjects. After anodal stimulation of the left hemisphere the increase of the MEP amplitudes was stronger in right handed subjects than in left and mixed handed subjects. Interestingly, after cathodal stimulation of the left hemisphere this difference was less marked. The stimulation of the right hemisphere showed the same tendency, but results were not significant., Conclusions: For the first time, we are able to demonstrate that the modulating effects of tDCS on corticospinal excitability differ moderately in the left-and mixed-handed population compared to right-handed subjects. The shown differences according to handedness should be taken into account in further studies.

This paper outlines the grand challenges in global sustainability research and the objectives of the FP7 Future Internet PPP program within the Digital Agenda for Europe. Large user communities are generating significant amounts of valuable environmental observations at local and regional scales using the devices and services of the Future Internet. These communities' environmental observations represent a wealth of information which is currently hardly used or used only in isolation and therefore in need of integration with other information sources. Indeed, this very integration will lead to a paradigm shift from a mere Sensor Web to an Observation Web with semantically enriched content emanating from sensors, environmental simulations and citizens. The paper also describes the research challenges to realize the Observation Web and the associated environmental enablers for the Future Internet. Such an environmental enabler could for instance be an electronic sensing device, a web-service application, or even a social networking group affording or facilitating the capability of the Future Internet applications to consume, produce, and use environmental observations in cross-domain applications. The term "envirofied" Future Internet is coined to describe this overall target that forms a cornerstone of work in the Environmental Usage Area within the Future Internet PPP program. Relevant trends described in the paper are the usage of ubiquitous sensors (anywhere), the provision and generation of information by citizens, and the convergence of real and virtual realities to convey understanding of environmental observations. The paper addresses the technical challenges in the Environmental Usage Area and the need for designing multi-style service oriented architecture. Key topics are the mapping of requirements to capabilities, providing scalability and robustness with implementing context aware information retrieval. Another essential research topic is handling data fusion and model based computation, and the related propagation of information uncertainty. Approaches to security, standardization and harmonization, all essential for sustainable solutions, are summarized from the perspective of the Environmental Usage Area. The paper concludes with an overview of emerging, high impact applications in the environmental areas concerning land ecosystems (biodiversity), air quality (atmospheric conditions) and water ecosystems (marine asset management).

The pharmacologic treatment for cancer must adhere to complex, finely orchestrated treatment plans, including not only chemotherapy medications, but pre/post-hydration, anti-emetics, anti-anxiety, and other medications that are given before, during and after chemotherapy doses. The treatment plans specify the medications and dictate precise dosing, frequency, and timing. This is a challenge to most Computerized Physician Order Entry (CPOE), Pharmacy and Electronic Medication Administration record (eMAR) Systems. Medications are scheduled on specific dates, referred to as chemo days, from the onset of the treatment, and precisely timed on the designated chemo day. For patients enrolled in research protocols, the adherence to the defined schedule takes on additional import, since variation is a violation of the protocol. If the oncologist determines that medications must be administered outside the defined constraints, the patient must be un-enrolled from the protocol and the course of therapy is re-written. Pharmacy and eMAR systems utilized in processing chemotherapy medications must be able to support the intricate relationships between each drug defined in the treatment plans.

Background: Most patients with symptomatic sinus node disease (SND) receive DDDR pacemakers (PM) in order to cover SND and atrioventricular (AV) block from the outset. But the concern about adverse effects of right ventricular pacing (RVP) is increasing. So far, data on the incidence of AV block in SND are based on clinical events. The study undertakes to assess and appraise AV block and atrial tachyarrhythmias (AT) from memory and electrograms of a dual-chamber PM set to an AAIR-DDDR switch mode (AAISafeR)., Methods: A dual-chamber PM incorporating the AAISafeR mode was implanted in 58 patients (70 +/- 10 years, 28 males) with SND, but without AV block >I. AV block and AT episodes were retrieved from the PM memory and validated from electrograms. AV block episodes were classified potentially relevant while comprising AV block III or AV block I/II during exercise., Results: The patients experienced a median of 90 (interquartile range 7-1,084) commutations. Possibly relevant AV block occurred in 32 patients (55%). Validation revealed high-quality PM-based categorization. The RVP prevalence was 0% (0-16%). The median AT prevalence was 0.03 (0-26) min/day. RVP was the only multivariate predictor of AT (P = 0.001)., Conclusions: Potentially relevant AV block occurs frequently in patients with SND. Nonetheless, the RVP prevalence is kept low through the AAISafeR mode. The protection of SND patients with demand-actuated ventricular pacing appears reasonable. The AT prevalence is low in SND patients treated by the AAISafeR mode. Even low RVP proportions appear to favor AT. Prospective evaluation is needed.

The scenario of lithopanspermia describes the viable transport of microorganisms via meteorites. To test the first step of lithopanspermia, i.e., the impact ejection from a planet, systematic shock recovery experiments within a pressure range observed in martian meteorites (5-50 GPa) were performed with dry layers of microorganisms (spores of Bacillus subtilis, cells of the endolithic cyanobacterium Chroococcidiopsis, and thalli and ascocarps of the lichen Xanthoria elegans) sandwiched between gabbro discs (martian analogue rock). Actual shock pressures were determined by refractive index measurements and Raman spectroscopy, and shock temperature profiles were calculated. Pressure-effect curves were constructed for survival of B. subtilis spores and Chroococcidiopsis cells from the number of colony-forming units, and for vitality of the photobiont and mycobiont of Xanthoria elegans from confocal laser scanning microscopy after live/dead staining (FUN-I). A vital launch window for the transport of rock-colonizing microorganisms from a Mars-like planet was inferred, which encompasses shock pressures in the range of 5 to about 40 GPa for the bacterial endospores and the lichens, and a more limited shock pressure range for the cyanobacterium (from 5-10 GPa). The results support concepts of viable impact ejections from Mars-like planets and the possibility of reseeding early Earth after asteroid cataclysms.

Lipopolysaccharide (LPS) treatment of resident liver macrophages resulted in a coordinated enhanced expression of cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase (COX)-2 and prostaglandin E(2)-synthase. LPS-pretreated liver macrophages showed a higher release of PGE(2) after zymosan, phorbol ester and A23187, of PGF(2alpha) after zymosan and A23187, whereas the release of thromboxane B(2) and PGD(2) was unchanged. Inhibition of COX-1 and -2 by specific inhibitors (SC560, SC236) inhibited the prostanoid release between 50-80% and 20-40%, respectively, indicating a predominant role for COX-1. In detail (1) the zymosan-induced release of all prostanoids was inhibited to a similar degree by the COX-1 inhibitor (about 70%) and the COX-2 inhibitor (20-30%), (2) PGE(2) release after all stimuli was inhibited to a greater extent by SC560 (70-90%) compared to SC236 (5-30%), (3) the phorbol ester- and A23187-induced release of PGF(2alpha) and PGD(2) was inhibited equally (40-50%) by both inhibitors, (3) TxB(2) release after phorbol ester and A23187 was inhibited by SC560 by 50 and 30%, and by SC236 by 50 and 70%, respectively. cPLA(2), COX-1 and -2, and the final prostanoid synthases were found in different subcellular fractions. These results indicate, that the functional coupling of COX-1 and -2 to final prostanoid synthases depends on the stimulation of the cells.

This study examines the distribution, understanding and objectives of nursing visits as well as the implementation and the experience with nursing visits in 87 hospitals in North Germany (Bremen, Lower Saxony, Hamburg, Schleswig-Holstein and Mecklenburg-Western Pomerania). The survey was conducted using a questionnaire. It was found that nursing visits are implemented in 31% of the departments. By means of the nursing visit the patients are involved in the nursing process. The objectives of nursing visits are patient orientation. and the improvement of the nursing quality. The nursing visit is criticised because of both the level of organisation and the time spent on nursing visits as well as the lack of training, maintaining confidentiality and questions of data protection. The study contributes to a better understanding of nursing visits and a clearer definition of the term. It is the first empirical study of this type that has been conducted in Germany.