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Background: The human chromosomal region 9p21.3 has been shown to be strongly associated with Coronary Heart Disease (CHD) in several Genome-wide Association Studies (GWAS). Recently, this region has also been shown to be associated with Aggressive Periodontitis (AgP), strengthening the hypothesis that the established epidemiological association between periodontitis and CHD is caused by a shared genetic background, in addition to common environmental and behavioural risk factors. However, the size of the analyzed cohorts in this primary analysis was small compared to other association studies on complex diseases. Using our own AgP cohort, we attempted to confirm the described associations for the chromosomal region 9p21.3. Methods: We analyzed our cohort consisting of patients suffering from the most severe form of AgP, generalized AgP (gAgP) (n = 130) and appropriate periodontally healthy control individuals (n = 339) by genotyping four tagging SNPs (rs2891168, rs1333042, rs1333048 and rs496892), located in the chromosomal region 9p21.3, that have been associated with AgP. Results: The results confirmed significant associations between three of the four SNPs and gAgP. The combination of our results with those from the study which described this association for the first time in a meta-analysis of the four tagging SNPs produced clearly lower p-values compared with the results of each individual study. According to these results, the most plausible genetic model for the association of all four tested SNPs with gAgP seems to be the multiplicative one. Conclusion: We positively replicated the finding of an association between the chromosomal region 9p21.3 and gAgP. This result strengthens support for the hypothesis that shared susceptibility genes within this chromosomal locus might be involved in the pathogenesis of both CHD and gAgP.
Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.
Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.
Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.
Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.
Objectives: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.
Methods: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.
Results: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.
Conclusions: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
Clinical trial registration number: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
Background: The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care.
Methods: The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre- and post-interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct-to-center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke-specific in situ simulation training. Primary outcome measure was the ‘door-to-needle’ time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre-existing treatment algorithm.
Results: The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre-intervention (interquartile range [IQR] 25–43 min) to 33 min (IQR 23–39 min, p = 0.03) post-intervention achieved by simulation-experienced stroke teams. Concerning EVT, we found significantly shorter door-to-groin times in patients who were treated by teams with simulation experience as compared to simulation-naive teams in the post-interventional phase (−21 min, simulation-naive: 95 min, IQR 69–111 vs. simulation-experienced: 74 min, IQR 51–92, p = 0.04).
Conclusion: An intervention combining workflow refinement and simulation-based stroke team training has the potential to improve process times in acute stroke care.
Aim: To evaluate the ability of PillCamColon2 to visualize colonic segments missed by incomplete optical colonoscopy (OC) and to assess the diagnostic yield.
Methods: This prospective multicentre study included 81 patients from nine centres who underwent second-generation colon capsule endoscopy (CCE) following incomplete OC performed by an experienced gastroenterologist (> 1000 colonoscopies). Patients with stenosis were excluded. According to patient preferences, CCE was performed the following day (protocol A) after staying on clear liquids and 0.75 L Moviprep in the morning or within 30 d after new split-dose Moviprep (protocol B). Boosts consisted of 0.75 L and 0.25 L Moviprep, and phospho-soda was given as a rescue if the capsule was not excreted after seven hours.
Results: Seventy-four patients were analysed (51% of them in group A; 49% in group B). Bowel cleansing was adequate in 67% of cases, and CCE could visualize colonic segments missed by incomplete colonoscopy in 90% of patients under protocol A and 97% of patients under protocol B (P = 0.35, n.s.). Significant polyps including adenocarcinoma were detected in 24% of cases. Detection rates for all polyps and significant polyps per patient were similar in both protocols. Polyps were found predominantly in the right colon (86%) in segments that were not reached by OC. Extracolonic findings - such as reflux esophagitis, suspected Barrett esophagus, upper GI-bleeding, gastric polyps, gastric erosions and angiectasia - were detected in eight patients. PillCamColon2 capsule was retained in the ileum of one patient (1.4%) without symptoms and removed during an uneventful resection for unknown Crohn’s disease that was diagnosed as the cause of anemia, which was the indication for colonoscopy. CCE was well tolerated. One patient suffered from self-limiting vomiting after consuming the phospho-soda.
Conclusion: Second-generation CCE using a low-volume preparation is useful after incomplete OC, and it allows for the detection of additional relevant findings, but cleansing efficiency could be improved.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
In high-energy heavy-ion collisions, partonic collectivity is evidenced by the constituent quark number scaling of elliptic flow anisotropy for identified hadrons. A breaking of this scaling and dominance of baryonic interactions is found for identified hadron collective flow measurements in √sNN = 3 GeV Au+Au collisions. In this paper, we report measurements of the first- and second-order azimuthal anisotropic parameters, v1 and v2, of light nuclei (d, t, 3He, 4He) produced in √sNN = 3 GeV Au+Au collisions at the STAR experiment. An atomic mass number scaling is found in the measured v1 slopes of light nuclei at mid-rapidity. For the measured v2 magnitude, a strong rapidity dependence is observed. Unlike v2 at higher collision energies, the v2 values at mid-rapidity for all light nuclei are negative and no scaling is observed with the atomic mass number. Calculations by the Jet AA Microscopic Transport Model (JAM), with baryonic mean-field plus nucleon coalescence, are in good agreement with our observations, implying baryonic interactions dominate the collective dynamics in 3 GeV Au+Au collisions at RHIC.
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
The STAR Collaboration reports measurements of back-to-back azimuthal correlations of di-π0s produced at forward pseudorapidities (2.6<η<4.0) in p+p, p+Al, and p+Au collisions at a center-of-mass energy of 200 GeV. We observe a clear suppression of the correlated yields of back-to-back π0 pairs in p+Al and p+Au collisions compared to the p+p data. The observed suppression of back-to-back pairs as a function of event activity and transverse momentum suggests nonlinear gluon dynamics arising at high parton densities. The larger suppression found in p+Au relative to p+Al collisions exhibits a dependence of the saturation scale, Q2s, on the mass number, A. The suppression in high-activity p+Au collisions is consistent with theoretical predictions including gluon saturation effects.
Observation of directed flow of hypernuclei Λ³H and Λ⁴H in √sNN = 3 GeV Au+Au collisions at RHIC
(2023)
We report here the first observation of directed flow (v1) of the hypernuclei 3ΛH and 4ΛH in mid-central Au+Au collisions at sNN−−−√ = 3 GeV at RHIC. These data are taken as part of the beam energy scan program carried out by the STAR experiment. From 165 × 106 events in 5%-40% centrality, about 8400 3ΛH and 5200 4ΛH candidates are reconstructed through two- and three-body decay channels. We observe that these hypernuclei exhibit significant directed flow. Comparing to that of light nuclei, it is found that the midrapidity v1 slopes of 3ΛH and 4ΛH follow baryon number scaling, implying that the coalescence is the dominant mechanism for these hypernuclei production in such collisions.
A linearly polarized photon can be quantized from the Lorentz-boosted electromagnetic field of a nucleus traveling at ultra-relativistic speed. When two relativistic heavy nuclei pass one another at a distance of a few nuclear radii, the photon from one nucleus may interact through a virtual quark-antiquark pair with gluons from the other nucleus forming a short-lived vector meson (e.g. ρ0). In this experiment, the polarization was utilized in diffractive photoproduction to observe a unique spin interference pattern in the angular distribution of ρ0→π+π− decays. The observed interference is a result of an overlap of two wave functions at a distance an order of magnitude larger than the ρ0 travel distance within its lifetime. The strong-interaction nuclear radii were extracted from these diffractive interactions, and found to be 6.53±0.06 fm (197Au) and 7.29±0.08 fm (238U), larger than the nuclear charge radii. The observable is demonstrated to be sensitive to the nuclear geometry and quantum interference of non-identical particles.
Notwithstanding decades of progress since Yukawa first developed a description of the force between nucleons in terms of meson exchange, a full understanding of the strong interaction remains a major challenge in modern science. One remaining difficulty arises from the non-perturbative nature of the strong force, which leads to the phenomenon of quark confinement at distances on the order of the size of the proton. Here we show that in relativistic heavy-ion collisions, where quarks and gluons are set free over an extended volume, two species of produced vector (spin-1) mesons, namely ϕ and K∗0, emerge with a surprising pattern of global spin alignment. In particular, the global spin alignment for ϕ is unexpectedly large, while that for K∗0 is consistent with zero. The observed spin-alignment pattern and magnitude for the ϕ cannot be explained by conventional mechanisms, while a model with a connection to strong force fields, i.e. an effective proxy description within the Standard Model and Quantum Chromodynamics, accommodates the current data. This connection, if fully established, will open a potential new avenue for studying the behaviour of strong force fields.
The strong force, as one of the four fundamental forces at work in the universe, governs interactions of quarks and gluons, and binds together the atomic nucleus. Notwithstanding decades of progress since Yukawa first developed a description of the force between nucleons in terms of meson exchange, a full understanding of the strong interaction remains a major challenge in modern science. One remaining difficulty arises from the non-perturbative nature of the strong force, which leads to the phenomenon of quark confinement at distance scales on the order of the size of the proton. Here we show that in relativistic heavy-ion collisions, where quarks and gluons are set free over an extended volume, two species of produced vector (spin-1) mesons, namely ϕ and K∗0, emerge with a surprising pattern of global spin alignment. In particular, the global spin alignment for ϕ is unexpectedly large, while that for K∗0 is consistent with zero. The observed spin-alignment pattern and magnitude for the ϕ cannot be explained by conventional mechanisms, while a model with strong force fields accommodates the current data. This is the first time that the strong force field is experimentally supported as a key mechanism that leads to global spin alignment. We extract a quantity proportional to the intensity of the field of the strong force. Within the framework of the Standard Model, where the strong force is typically described in the quark and gluon language of Quantum Chromodynamics, the field being considered here is an effective proxy description. This is a qualitatively new class of measurement, which opens a new avenue for studying the behaviour of strong force fields via their imprint on spin alignment.
The strong force, as one of the four fundamental forces at work in the universe, governs interactions of quarks and gluons, and binds together the atomic nucleus. Notwithstanding decades of progress since Yukawa first developed a description of the force between nucleons in terms of meson exchange, a full understanding of the strong interaction remains a major challenge in modern science. One remaining difficulty arises from the non-perturbative nature of the strong force, which leads to the phenomenon of quark confinement at distance scales on the order of the size of the proton. Here we show that in relativistic heavy-ion collisions, where quarks and gluons are set free over an extended volume, two species of produced vector (spin-1) mesons, namely ϕ and K∗0, emerge with a surprising pattern of global spin alignment. In particular, the global spin alignment for ϕ is unexpectedly large, while that for K∗0 is consistent with zero. The observed spin-alignment pattern and magnitude for the ϕ cannot be explained by conventional mechanisms, while a model with strong force fields accommodates the current data. This is the first time that the strong force field is experimentally supported as a key mechanism that leads to global spin alignment. We extract a quantity proportional to the intensity of the field of the strong force. Within the framework of the Standard Model, where the strong force is typically described in the quark and gluon language of Quantum Chromodynamics, the field being considered here is an effective proxy description. This is a qualitatively new class of measurement, which opens a new avenue for studying the behaviour of strong force fields via their imprint on spin alignment.
Two-particle correlations on transverse rapidity in Au+Au collisions at √sNN = 200 GeV at STAR
(2022)
Two-particle correlation measurements projected onto two-dimensional, transverse rapidity coordinates (yT1,yT2), allow access to dynamical properties of the QCD medium produced in relativistic heavy-ion collisions that angular correlation measurements are not sensitive to. We report non-identified charged-particle correlations for Au + Au minimum-bias collisions at sNN−−−√ = 200 GeV taken by the STAR experiment at the Relativistic Heavy-Ion Collider (RHIC). Correlations are presented as 2D functions of transverse rapidity for like-sign, unlike-sign and all charged-particle pairs, as well as for particle pairs whose relative azimuthal angles lie on the near-side, the away-side, or at all relative azimuth. The correlations are constructed using charged particles with transverse momentum pT≥0.15 GeV/c, pseudorapidity from −1 to 1, and azimuthal angles from −π to π. The significant correlation structures that are observed evolve smoothly with collision centrality. The major correlation features include a saddle shape plus a broad peak with maximum near yT≈3, corresponding to pT≈ 1.5 GeV/c. The broad peak is observed in both like- and unlike-sign charge combinations and in near- and away-side relative azimuthal angles. The all-charge, all-azimuth correlation measurements are compared with the theoretical predictions of {\sc hijing} and {\sc epos}. The results indicate that the correlations for peripheral to mid-central collisions can be approximately described as a superposition of nucleon + nucleon collisions with minimal effects from the QCD medium. Strong medium effects are indicated in mid- to most-central collisions.
The STAR Collaboration reports measurements of back-to-back azimuthal correlations of di-π0s produced at forward pseudorapidities (2.6<η<4.0) in p+p, p+Al, and p+Au collisions at a center-of-mass energy of 200 GeV. We observe a clear suppression of the correlated yields of back-to-back π0 pairs in p+Al and p+Au collisions compared to the p+p data. The observed suppression of back-to-back pairs as a function of transverse momentum suggests nonlinear gluon dynamics arising at high parton densities. The larger suppression found in p+Au relative to p+Al collisions exhibits a dependence of the saturation scale, Q2s, on the mass number, A. A linear scaling of the suppression with A1/3 is observed with a slope of −0.09 ± 0.01.
The linear and mode-coupled contributions to higher-order anisotropic flow are presented for Au+Au collisions at sNN−−−√ = 27, 39, 54.4, and 200 GeV and compared to similar measurements for Pb+Pb collisions at the Large Hadron Collider (LHC). The coefficients and the flow harmonics' correlations, which characterize the linear and mode-coupled response to the lower-order anisotropies, indicate a beam energy dependence consistent with an influence from the specific shear viscosity (η/s). In contrast, the dimensionless coefficients, mode-coupled response coefficients, and normalized symmetric cumulants are approximately beam-energy independent, consistent with a significant role from initial-state effects. These measurements could provide unique supplemental constraints to (i) distinguish between different initial-state models and (ii) delineate the temperature (T) and baryon chemical potential (μB) dependence of the specific shear viscosity ηs(T,μB).
The elliptic (v2) and triangular (v3) azimuthal anisotropy coefficients in central 3He+Au, d+Au, and p+Au collisions at sNN−−−√ = 200 GeV are measured as a function of transverse momentum (pT) at mid-rapidity (|η|<0.9), via the azimuthal angular correlation between two particles both at |η|<0.9. While the v2(pT) values depend on the colliding systems, the v3(pT) values are system-independent within the uncertainties, suggesting an influence on eccentricity from sub-nucleonic fluctuations in these small-sized systems. These results also provide stringent constraints for the hydrodynamic modeling of these systems.
The linear and mode-coupled contributions to higher-order anisotropic flow are presented for Au+Au collisions at √sN N = 27, 39, 54.4, and 200 GeV and compared to similar measurements for Pb+Pb collisions at the Large Hadron Collider (LHC). The coefficients and the flow harmonics’ correlations, which characterize the linear and mode-coupled response to the lower-order anisotropies, indicate a beam energy dependence consistent with an influence from the specific shear viscosity (η/s). In contrast, the dimensionless coefficients, mode-coupled response coefficients, and normalized symmetric cumulants are approximately beam-energy independent, consistent with a significant role from initialstate effects. These measurements could provide unique supplemental constraints to (i) distinguish between different initial-state models and (ii) delineate the temperature (T ) and baryon chemical potential (μB ) dependence of the specific shear viscosity η s (T ,μB ).
We report measurements of the longitudinal double-spin asymmetry, ALL, for inclusive jet and dijet production in polarized proton-proton collisions at midrapidity and center-of-mass energy s√ = 510 GeV, using the high luminosity data sample collected by the STAR experiment in 2013. These measurements complement and improve the precision of previous STAR measurements at the same center-of-mass energy that probe the polarized gluon distribution function at partonic momentum fraction 0.015 ≲x≲ 0.25. The dijet asymmetries are separated into four jet-pair topologies, which provide further constraints on the x dependence of the polarized gluon distribution function. These measurements are in agreement with previous STAR measurements and with predictions from current next-to-leading order global analyses. They provide more precise data at low dijet invariant mass that will better constraint the shape of the polarized gluon distribution function of the proton.
We report measurements of the longitudinal double-spin asymmetry, ALL, for inclusive jet and dijet production in polarized proton-proton collisions at midrapidity and center-of-mass energy s√ = 510 GeV, using the high luminosity data sample collected by the STAR experiment in 2013. These measurements complement and improve the precision of previous STAR measurements at the same center-of-mass energy that probe the polarized gluon distribution function at partonic momentum fraction 0.015 ≲x≲ 0.25. The dijet asymmetries are separated into four jet-pair topologies, which provide further constraints on the x dependence of the polarized gluon distribution function. These measurements are in agreement with previous STAR measurements and with predictions from current next-to-leading order global analyses. They provide more precise data at low dijet invariant mass that will better constraint the shape of the polarized gluon distribution function of the proton.
We present the first measurements of transverse momentum spectra of π±, K±, p(p¯) at midrapidity (|y|<0.1) in U+U collisions at √sNN = 193 GeV with the STAR detector at the Relativistic Heavy Ion Collider (RHIC). The centrality dependence of particle yields, average transverse momenta, particle ratios and kinetic freeze-out parameters are discussed. The results are compared with the published results from Au+Au collisions at sNN−−−−√= 200 GeV in STAR. The results are also compared to those from A Multi Phase Transport (AMPT) model.
Monetary policy communication is particularly important during unconventional times, because high uncertainty about the economy, the introduction of new policy tools and possible limits to the central bank’s toolkit could hamper the predictability of policy actions. We study how monetary policy communication should and has worked under such circumstances. Our main results relate to announcements of asset purchase programmes and the use of forward guidance. We show that announcements of asset purchase programmes have lowered market uncertainty, particularly when accompanied by a contextual release of implementation details such as the envisaged size of the programme. We also show that forward guidance reduces uncertainty more effectively when it is state‐contingent or when it provides guidance about a long horizon than when it is open‐ended or covers only a short horizon, and that the credibility of forward guidance is strengthened if the central bank also has embarked on an asset purchase programme.
Introduction: Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.
Methods: Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.
Results: During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), alpha-ketoglutarate (35.3 microEq/L), fumarate (6.2 microEq/L), sulfate (0.1 mEq/L), and urate (55.9 microEq/L) after shock induction.
Conclusion: Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.
Reduced Cl− conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+ channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK−/−) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK−/− mice resulted in a significantly decreased T90/10 in presence of 9-AC. Paxilline significantly shortened T90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.
Background and purpose: Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods: The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD-EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m2. eGFR dynamics were classified based on two in-hospital values as “stable normal” (≥60 ml/min/1.73 m2), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m2), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m2), and “stable decreased” (<60 ml/min/1.73 m2). The composite endpoint (stroke, major bleeding, myocardial infarction, all-cause death) was assessed after 24 months. We estimated hazard ratios in confounder-adjusted models.
Results: Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m2 at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all-cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions: In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.
Purpose: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging.
Experimental design: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial.
Results: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76).
Conclusion: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy.
Translational relevance: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.
Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim.
Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago.
Results: During hospitalization, the platelet count was measured above 330,000/μl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved.
Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.
Water-filtered infrared-A (wIRA) as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing and infection defense.
wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.
A prospective, randomized, controlled, double-blind study with 111 patients after major abdominal surgery at the University Hospital Heidelberg, Germany, showed with 20 minutes irradiation twice a day (starting on the second postoperative day) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a significant and relevant pain reduction combined with a markedly decreased required dose of analgesics: during 230 single irradiations with wIRA(+VIS) the pain decreased without any exception (median of decrease of pain on postoperative days 2-6 was 13.4 on a 100 mm visual analog scale VAS 0-100), while pain remained unchanged in the control group (p<0.001). The required dose of analgesics was 57-70% lower in the subgroups with wIRA(+VIS) compared to the control subgroups with only VIS (median 598 versus 1398 ml ropivacaine, p<0.001, for peridural catheter analgesia; 31 versus 102 mg piritramide, p=0.001, for patient-controlled analgesia; 3.4 versus 10.2 g metamizole, p=0.005, for intravenous and oral analgesia). During irradiation with wIRA(+VIS) the subcutaneous oxygen partial pressure rose markedly by approximately 30% and the subcutaneous temperature by approximately 2.7°C (both in a tissue depth of 2 cm), whereas both remained unchanged in the control group: after irradiation the median of the subcutaneous oxygen partial pressure was 41.6 (with wIRA) versus 30.2 mm Hg in the control group (p<0.001), the median of the subcutaneous temperature was 38.9 versus 36.4°C (p<0.001). The overall evaluation of the effect of irradiation, including wound healing, pain and cosmesis, assessed on a VAS (0-100 with 50 as indifferent point of no effect) by the surgeon (median 79.0 versus 46.8, p<0.001) or the patient (79.0 versus 50.2, p<0.001) was markedly better in the group with wIRA compared to the control group. This was also true for single aspects: Wound healing assessed on a VAS by the surgeon (median 88.6 versus 78.5, p<0.001) or the patient (median 85.8 versus 81.0, p=0.040, trend) and cosmetic result assessed on a VAS by the surgeon (median 84.5 versus 76.5, p<0.001) or the patient (median 86.7 versus 73.6, p=0.001). In addition there was a trend in favor of the wIRA group to a lower rate of total wound infections (3 of 46, approximately 7%, versus 7 of 48, approximately 15%, p=0.208) including late infections after discharge, caused by the different rate of late infections after discharge: 0 of 46 in the wIRA group and 4 of 48 in the control group. And there was a trend towards a shorter postoperative hospital stay: 9 days in the wIRA group versus 11 days in the control group (p=0.037). The principal finding of this study was that postoperative irradiation with wIRA can improve even a normal wound healing process.
A prospective, randomized, controlled, double-blind study with 45 severely burned children at the Children’s Hospital Park Schönfeld, Kassel, Germany, showed with 30 minutes irradiation once a day (starting on the first day, day of burn as day 1) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a markedly faster reduction of wound size. On the fifth day (after 4 days with irradiation) decision was taken, whether surgical debridement of necrotic tissue was necessary because of deeper (second degree, type b) burns (11 of 21 in the group with wIRA, 14 of 24 in the control group) or non-surgical treatment was possible (second degree, type a, burns). The patients treated conservatively were kept within the study and irradiated till complete reepithelialization. The patients in the group with wIRA showed a markedly faster reduction of wound area: a median reduction of wound size of 50% was reached already after 7 days compared to 9 days in the control group, a median reduction of wound size of 90% was already achieved after 9 days compared to 13 days in the control group. In addition the group with wIRA showed superior results till 3 months after the burn in terms of the overall surgical assessment of the wound, cosmesis, and assessment of effects of irradiation compared to the control group.
In a prospective, randomized, controlled study with 12 volunteers at the University Medical Center Charité, Berlin, Germany, within each volunteer 4 experimental superficial wounds (5 mm diameter) as an acute wound model were generated by suction cup technique, removing the roof of the blister with a scalpel and a sterile forceps (day 1). 4 different treatments were used and investigated during 10 days: no therapy, only wIRA(+VIS) (approximately 75% wIRA, 25% VIS; 30 minutes irradiation once a day), only dexpanthenol (= D-panthenol) cream once a day, wIRA(+VIS) and dexpanthenol cream once a day. Healing of the small experimental wounds was from a clinical point of view excellent with all 4 treatments. Therefore there were only small differences between the treatments with slight advantages of the combination wIRA(+VIS) and dexpanthenol cream and of dexpanthenol cream alone concerning relative change of wound size and assessment of feeling of the wound area. However laser scanning microscopy with a scoring system revealed differences between the 4 treatments concerning the formation of the stratum corneum (from first layer of corneocytes to full formation) especially on the days 5-7: fastest formation of the stratum corneum was seen in wounds treated with wIRA(+VIS) and dexpanthenol cream, second was wIRA(+VIS) alone, third dexpanthenol cream alone and last were untreated wounds. Bacterial counts of the wounds (taken every 2 days) showed, that wIRA(+VIS) and the combination of wIRA(+VIS) with dexpanthenol cream were able to inhibit the colonisation with physiological skin flora up to day 5 when compared with the two other groups (untreated group and group with dexpanthenol cream alone). At any investigated time, the amount of colonisation under therapy with wIRA(+VIS) alone was lower (interpreted as more suppressed) compared with the group with wIRA(+VIS) and dexpanthenol cream.
During rehabilitation after hip and knee endoprosthetic operations the resorption of wound seromas and wound hematomas was both clinically and sonographically faster and pain was reduced by irradiation with wIRA(+VIS).
wIRA can be used successfully for persistent postoperative pain e.g. after thoracotomy.
As perspectives for wIRA it seems clinically prudent to use wIRA both pre- and postoperatively, e.g. in abdominal and thoracic operations. wIRA can be used preoperatively (e.g. during 1-2 weeks) to precondition donor and recipient sites of skin flaps, transplants or partial-thickness skin grafts, and postoperatively to improve wound healing and to decrease pain, inflammation and infections at all mentioned sites. wIRA can be used to support routine pre- or intraoperative antibiotic administration or it might even be discussed to replace this under certain conditions by wIRA.
Water-filtered infrared-A (wIRA) as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing and infection defense.
wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.
A prospective, randomized, controlled, double-blind study with 111 patients after major abdominal surgery at the University Hospital Heidelberg, Germany, showed with 20 minutes irradiation twice a day (starting on the second postoperative day) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a significant and relevant pain reduction combined with a markedly decreased required dose of analgesics: during 230 single irradiations with wIRA(+VIS) the pain decreased without any exception (median of decrease of pain on postoperative days 2-6 was 13.4 on a 100 mm visual analog scale VAS 0-100), while pain remained unchanged in the control group (p<0.001). The required dose of analgesics was 57-70% lower in the subgroups with wIRA(+VIS) compared to the control subgroups with only VIS (median 598 versus 1398 ml ropivacaine, p<0.001, for peridural catheter analgesia; 31 versus 102 mg piritramide, p=0.001, for patient-controlled analgesia; 3.4 versus 10.2 g metamizole, p=0.005, for intravenous and oral analgesia). During irradiation with wIRA(+VIS) the subcutaneous oxygen partial pressure rose markedly by approximately 30% and the subcutaneous temperature by approximately 2.7°C (both in a tissue depth of 2 cm), whereas both remained unchanged in the control group: after irradiation the median of the subcutaneous oxygen partial pressure was 41.6 (with wIRA) versus 30.2 mm Hg in the control group (p<0.001), the median of the subcutaneous temperature was 38.9 versus 36.4°C (p<0.001). The overall evaluation of the effect of irradiation, including wound healing, pain and cosmesis, assessed on a VAS (0-100 with 50 as indifferent point of no effect) by the surgeon (median 79.0 versus 46.8, p<0.001) or the patient (79.0 versus 50.2, p<0.001) was markedly better in the group with wIRA compared to the control group. This was also true for single aspects: Wound healing assessed on a VAS by the surgeon (median 88.6 versus 78.5, p<0.001) or the patient (median 85.8 versus 81.0, p=0.040, trend) and cosmetic result assessed on a VAS by the surgeon (median 84.5 versus 76.5, p<0.001) or the patient (median 86.7 versus 73.6, p=0.001). In addition there was a trend in favor of the wIRA group to a lower rate of total wound infections (3 of 46, approximately 7%, versus 7 of 48, approximately 15%, p=0.208) including late infections after discharge, caused by the different rate of late infections after discharge: 0 of 46 in the wIRA group and 4 of 48 in the control group. And there was a trend towards a shorter postoperative hospital stay: 9 days in the wIRA group versus 11 days in the control group (p=0.037). The principal finding of this study was that postoperative irradiation with wIRA can improve even a normal wound healing process.
A prospective, randomized, controlled, double-blind study with 45 severely burned children at the Children’s Hospital Park Schönfeld, Kassel, Germany, showed with 30 minutes irradiation once a day (starting on the first day, day of burn as day 1) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a markedly faster reduction of wound size. On the fifth day (after 4 days with irradiation) decision was taken, whether surgical debridement of necrotic tissue was necessary because of deeper (second degree, type b) burns (11 of 21 in the group with wIRA, 14 of 24 in the control group) or non-surgical treatment was possible (second degree, type a, burns). The patients treated conservatively were kept within the study and irradiated till complete reepithelialization. The patients in the group with wIRA showed a markedly faster reduction of wound area: a median reduction of wound size of 50% was reached already after 7 days compared to 9 days in the control group, a median reduction of wound size of 90% was already achieved after 9 days compared to 13 days in the control group. In addition the group with wIRA showed superior results till 3 months after the burn in terms of the overall surgical assessment of the wound, cosmesis, and assessment of effects of irradiation compared to the control group.
In a prospective, randomized, controlled study with 12 volunteers at the University Medical Center Charité, Berlin, Germany, within each volunteer 4 experimental superficial wounds (5 mm diameter) as an acute wound model were generated by suction cup technique, removing the roof of the blister with a scalpel and a sterile forceps (day 1). 4 different treatments were used and investigated during 10 days: no therapy, only wIRA(+VIS) (approximately 75% wIRA, 25% VIS; 30 minutes irradiation once a day), only dexpanthenol (= D-panthenol) cream once a day, wIRA(+VIS) and dexpanthenol cream once a day. Healing of the small experimental wounds was from a clinical point of view excellent with all 4 treatments. Therefore there were only small differences between the treatments with slight advantages of the combination wIRA(+VIS) and dexpanthenol cream and of dexpanthenol cream alone concerning relative change of wound size and assessment of feeling of the wound area. However laser scanning microscopy with a scoring system revealed differences between the 4 treatments concerning the formation of the stratum corneum (from first layer of corneocytes to full formation) especially on the days 5-7: fastest formation of the stratum corneum was seen in wounds treated with wIRA(+VIS) and dexpanthenol cream, second was wIRA(+VIS) alone, third dexpanthenol cream alone and last were untreated wounds. Bacterial counts of the wounds (taken every 2 days) showed, that wIRA(+VIS) and the combination of wIRA(+VIS) with dexpanthenol cream were able to inhibit the colonisation with physiological skin flora up to day 5 when compared with the two other groups (untreated group and group with dexpanthenol cream alone). At any investigated time, the amount of colonisation under therapy with wIRA(+VIS) alone was lower (interpreted as more suppressed) compared with the group with wIRA(+VIS) and dexpanthenol cream.
During rehabilitation after hip and knee endoprosthetic operations the resorption of wound seromas and wound hematomas was both clinically and sonographically faster and pain was reduced by irradiation with wIRA(+VIS).
wIRA can be used successfully for persistent postoperative pain e.g. after thoracotomy.
As perspectives for wIRA it seems clinically prudent to use wIRA both pre- and postoperatively, e.g. in abdominal and thoracic operations. wIRA can be used preoperatively (e.g. during 1-2 weeks) to precondition donor and recipient sites of skin flaps, transplants or partial-thickness skin grafts, and postoperatively to improve wound healing and to decrease pain, inflammation and infections at all mentioned sites. wIRA can be used to support routine pre- or intraoperative antibiotic administration or it might even be discussed to replace this under certain conditions by wIRA.
Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
The establishment and maintenance of protected areas (PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting protected areas based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences, as well as real-time comparison of the selected areas that result from such different priorities. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between species protection and ecosystem integrity. Outputs indicate that decision makers frequently face trade-offs among conflicting objectives. Nevertheless, we show that transparent decision-support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.
Background & Aims: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients.
Methods: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort.
Results: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly.
Conclusions: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.
Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested.
None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival.
Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain.
Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein.
Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.
Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
The single nucleotide polymorphism 118A>G of the human micro-opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the mu-opioid receptor-specific agonist DAMGO, we analyzed the micro-opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (SII) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D micro-opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the SII region of homo- and heterozygous carriers of the variant 118G allele (n=18), DAMGO was only 62% as efficient (p=0.002) as in homozygous carriers of the wild-type 118A allele (n=15). In contrast, the number of [3H]DAMGO binding sites was unaffected. Hence, the micro-opioid receptor G-protein coupling efficacy in SII of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p<0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of mu-opioid receptor variant N40D.
Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP
(2015)
Loss of plasticity-related gene 1 (PRG-1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg-1 (R345T/mutPRG-1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss-of-PRG-1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG-1(+/-) mice, which are animal correlates of human PRG-1(+/mut) carriers, showed an altered cortical network function and stress-related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA-synthesizing molecule autotaxin. In line, EEG recordings in a human population-based cohort revealed an E/I balance shift in monoallelic mutPRG-1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress-related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate-dependent symptoms in psychiatric diseases.
Background and Purpose: The cyclic nucleotides cAMP and cGMP are ubiquitous second messengers regulating numerous biological processes. Malfunctional cNMP signalling is linked to diseases and thus is an important target in pharmaceutical research. The existing optogenetic toolbox in Caenorhabditis elegans is restricted to soluble adenylyl cyclases, the membrane-bound Blastocladiella emersonii CyclOp and hyperpolarizing rhodopsins; yet missing are membrane-bound photoactivatable adenylyl cyclases and hyperpolarizers based on K+ currents.
Experimental Approach: For the characterization of photoactivatable nucleotidyl cyclases, we expressed the proteins alone or in combination with cyclic nucleotide-gated channels in muscle cells and cholinergic motor neurons. To investigate the extent of optogenetic cNMP production and the ability of the systems to depolarize or hyperpolarize cells, we performed behavioural analyses, measured cNMP content in vitro, and compared in vivo expression levels.
Key Results: We implemented Catenaria CyclOp as a new tool for cGMP production, allowing fine-control of cGMP levels. We established photoactivatable membrane-bound adenylyl cyclases, based on mutated versions (“A-2x”) of Blastocladiella and Catenaria (“Be,” “Ca”) CyclOp, as N-terminal YFP fusions, enabling more efficient and specific cAMP signalling compared to soluble bPAC, despite lower overall cAMP production. For hyperpolarization of excitable cells by two-component optogenetics, we introduced the cAMP-gated K+-channel SthK from Spirochaeta thermophila and combined it with bPAC, BeCyclOp(A-2x), or YFP-BeCyclOp(A-2x). As an alternative, we implemented the B. emersonii cGMP-gated K+-channel BeCNG1 together with BeCyclOp.
Conclusion and Implications: We established a comprehensive suite of optogenetic tools for cNMP manipulation, applicable in many cell types, including sensory neurons, and for potent hyperpolarization.
The establishment and maintenance of protected areas(PAs) is viewed as a key action in delivering post-2020 biodiversity targets. PAs often need to meet a multitude of objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation. As available land and conservation funding are limited, optimizing resources by selecting the most beneficial PAs is vital. Here we present a decision support tool that enables a flexible approach to PA selection on a global scale, allowing different conservation objectives to be weighted and prioritized according to user-specified preferences. We apply the tool across 1347 terrestrial PAs and highlight frequent trade-offs among different objectives, e.g., between biodiversity protection and ecosystem integrity. These results indicate that decision makers must usually decide among conflicting objectives. To assist this our decision support tool provides an explicitly value-based approach that can help resolve such conflicts by considering divergent societal and political demands and values.
Establishing and maintaining protected areas (PAs) is a key action in delivering post-2020 biodiversity targets. PAs often need to meet multiple objectives, ranging from biodiversity protection to ecosystem service provision and climate change mitigation, but available land and conservation funding is limited. Therefore, optimizing resources by selecting the most beneficial PAs is vital. Here, we advocate for a flexible and transparent approach to selecting PAs based on multiple objectives, and illustrate this with a decision support tool on a global scale. The tool allows weighting and prioritization of different conservation objectives according to user-specified preferences as well as real-time comparison of the outcome. Applying the tool across 1,346 terrestrial PAs, we demonstrate that decision makers frequently face trade-offs among conflicting objectives, e.g., between species protection and ecosystem integrity. Nevertheless, we show that transparent decision support tools can reveal synergies and trade-offs associated with PA selection, thereby helping to illuminate and resolve land-use conflicts embedded in divergent societal and political demands and values.
Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.
Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).
Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).
Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.