Stringent test of QED with hydrogen-like tin.

Inner-shell electrons naturally sense the electric field close to the nucleus, which can reach extreme values beyond 1015 V cm-1 for the innermost electrons1. Especially in few-electron, highly charged ions, the interaction with the electromagnetic fields can be accurately calculated within quantum electrodynamics (QED), rendering these ions good candidates to test the validity of QED in strong fields. Consequently, their Lamb shifts were intensively studied in the past several decades2,3. Another approach is the measurement of gyromagnetic factors (g factors) in highly charged ions4-7. However, so far, either experimental accuracy or small field strength in low-Z ions5,6 limited the stringency of these QED tests. Here we report on our high-precision, high-field test of QED in hydrogen-like 118Sn49+. The highly charged ions were produced with the Heidelberg electron beam ion trap (EBIT)8 and injected into the ALPHATRAP Penning-trap setup9, in which the bound-electron g factor was measured with a precision of 0.5 parts per billion (ppb). For comparison, we present state-of-the-art theory calculations, which together test the underlying QED to about 0.012%, yielding a stringent test in the strong-field regime. With this measurement, we challenge the best tests by means of the Lamb shift and, with anticipated advances in the g-factor theory, surpass them by more than an order of magnitude.

High-Precision Determination of g Factors and Masses of

We present the measurements of individual bound electron g factors of ^{20}Ne^{9+} and ^{22}Ne^{9+} on the relative level of 0.1 parts per billion. The comparison with theory represents the most stringent test of bound-state QED in strong electric fields. A dedicated mass measurement results in m(^{20}Ne)=19.992 440 168 77(9) u, which improves the current literature value by a factor of 18, disagrees by 4 standard deviations, and represents the most precisely measured mass value in atomic mass units. Together, these measurements yield an electron mass on the relative level of 0.1 ppb with m_{e}=5.485 799 090 99(59)×10^{-4} u as well as a factor of seven improved m(^{22}Ne)=21.991 385 098 2(26) u.

[Pharmacological/pharmaceutical counseling in intensive care medicine]. / Die pharmakologische/pharmazeutische Visite in der Intensivmedizin.

Adequate pharmacotherapy in critically ill patients is challenging for many clinicians. Disease-related pathophysiological changes often lead to complex therapy strategies including many intensive care treatments (e.g. invasive ventilation, renal replacement therapy). These measures often influence drug prescribing and dosing. Therefore, in organ dysfunction such as renal and liver impairment reduced drug elimination has to be considered by adapting drug dosing towards elimination rates. Moreover, as intensive care medicine often includes the use of multiple drugs the risk for drug-drug interactions increases. The current article gives an overview about the complexity of individual pharmacotherapy in intensive care units whilst providing information for its clinical implementation.

Detection of metastable electronic states by Penning trap mass spectrometry.

State-of-the-art optical clocks1 achieve precisions of 10-18 or better using ensembles of atoms in optical lattices2,3 or individual ions in radio-frequency traps4,5. Promising candidates for use in atomic clocks are highly charged ions6 (HCIs) and nuclear transitions7, which are largely insensitive to external perturbations and reach wavelengths beyond the optical range8 that are accessible to frequency combs9. However, insufficiently accurate atomic structure calculations hinder the identification of suitable transitions in HCIs. Here we report the observation of a long-lived metastable electronic state in an HCI by measuring the mass difference between the ground and excited states in rhenium, providing a non-destructive, direct determination of an electronic excitation energy. The result is in agreement with advanced calculations. We use the high-precision Penning trap mass spectrometer PENTATRAP to measure the cyclotron frequency ratio of the ground state to the metastable state of the ion with a precision of 10-11-an improvement by a factor of ten compared with previous measurements10,11. With a lifetime of about 130 days, the potential soft-X-ray frequency reference at 4.96 × 1016 hertz (corresponding to a transition energy of 202 electronvolts) has a linewidth of only 5 × 10-8 hertz and one of the highest electronic quality factors (1024) measured experimentally so far. The low uncertainty of our method will enable searches for further soft-X-ray clock transitions8,12 in HCIs, which are required for precision studies of fundamental physics6.

Pertussis vaccination in mixed markets: Recommendations from the Global Pertussis Initiative.

The Global Pertussis Initiative is an expert scientific forum that publishes consensus recommendations concerning pertussis for many regions of the world. Here, we give recommendations for the primary vaccination of infants in those countries where whole-cell pertussis (wP)- and acellular pertussis (aP)-containing combination vaccines are used in parallel. A selective literature review was performed concerning the influence on safety, immunogenicity, and effectiveness of mixing wP- and aP-containing vaccines for primary immunization of infants. In addition, local data were collected from various countries and the results discussed in a face-to-face meeting. Very few data addressing issues of mixing combination vaccines were identified, and no data were available concerning the effectiveness or duration of protection. It was also found that pharmacovigilance data are scarce or lacking in those countries where they would be needed the most. We then identified frequent problems occurring in low- and middle-income countries (LMICs) where both vaccine types are used. Relying on local knowledge, we give practical recommendations for a variety of situations in different settings. Specific needs for additional data addressing these issues were also identified. International bodies, such as the World Health Organization (WHO), as well as vaccine producers should try to find ways to highlight the problems of mixing wP- and aP-containing combination vaccines with robust data. Countries are urged to improve on their pharmacovigilance for vaccines. For practicing physicians, our recommendations offer guidance when wP- and aP-containing vaccines are used in parallel during primary immunization.

Mass-Difference Measurements on Heavy Nuclides with an eV/c

First ever measurements of the ratios of free cyclotron frequencies of heavy, highly charged ions with Z>50 with relative uncertainties close to 10^{-11} are presented. Such accurate measurements have become realistic due to the construction of the novel cryogenic multi-Penning-trap mass spectrometer PENTATRAP. Based on the measured frequency ratios, the mass differences of five pairs of stable xenon isotopes, ranging from ^{126}Xe to ^{134}Xe, have been determined. Moreover, the first direct measurement of an electron binding energy in a heavy highly charged ion, namely of the 37th atomic electron in xenon, with an uncertainty of a few eV is demonstrated. The obtained value agrees with the calculated one using two independent, different implementations of the multiconfiguration Dirac-Hartree-Fock method. PENTATRAP opens the door to future measurements of electron binding energies in highly charged heavy ions for more stringent tests of bound-state quantum electrodynamics in strong electromagnetic fields and for an investigation of the manifestation of light dark matter in isotopic chains of certain chemical elements.

Production of highly charged ions of rare species by laser-induced desorption inside an electron beam ion trap.

This paper reports on the development and testing of a novel, highly efficient technique for the injection of very rare species into electron beam ion traps (EBITs) for the production of highly charged ions (HCI). It relies on in-trap laser-induced desorption of atoms from a sample brought very close to the electron beam resulting in a very high capture efficiency in the EBIT. We have demonstrated a steady production of HCI of the stable isotope 165Ho from samples of only 1012 atoms (∼300 pg) in charge states up to 45+. HCI of these species can be subsequently extracted for use in other experiments or stored in the trapping volume of the EBIT for spectroscopic measurements. The high efficiency of this technique extends the range of rare isotope HCIs available for high-precision atomic mass and spectroscopic measurements. A first application of this technique is the production of HCI of the synthetic radioisotope 163Ho for a high-precision measurement of the QEC-value of the electron capture in 163Ho within the "Electron Capture in Holmium" experiment [L. Gastaldo et al., J. Low Temp. Phys. 176, 876-884 (2014); L. Gastaldo et al., Eur. Phys. J.: Spec. Top. 226, 1623-1694 (2017)] (ECHo collaboration) ultimately leading to a measurement of the electron neutrino mass with an uncertainty on the sub electronvolt level.

Pertussis surveillance by small serosurveys of blood donors.

Serosurveys have established data about the distribution of immunoglobulin G (IgG)-antibodies to pertussis toxin (PT) in various populations. We tried to detect whether small serosurveys in blood donors could serve as a simple and inexpensive means to collect information about the circulation of Bordetella pertussis. We screened every donation in 307 adult blood donors aged 19-69 years for IgG-anti-PT by standardised enzyme-linked immunosorbent assays (ELISA), and the donors were followed between 2014 and 2016 for a total of 426 person-years. When we used a vertical survey with cut-offs of 100, 62.5 and 40 IU/ml, respectively, as an indicator for recent contacts with B. pertussis, nine (2.9%), 22 (7.2%) and 54 (17.6%) of donors had IgG-anti-PT titres above the respective levels. During the horizontal observation period of 426 person years, six significant increases and two conversions were found, which lead to an estimate of 1878 contacts/100.000 person-years (1.9% per year). Median and mean IgG-anti-PT concentrations remained relatively stable from year to year during the observation period. Our findings show that small serosurveys of blood donors offer a simple and cheap method for the surveillance of B. pertussis.

[Adequate anti-infective treatment : Importance of individual dosing and application]. / Adäquate Antiinfektivatherapie : Bedeutung der individuellen Dosierung und Applikation.

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

The importance of laboratory re-evaluation in cases of suspected child abuse - A case report.

In order to accurately diagnose child abuse or neglect, a physician needs to be familiar with diseases and medical conditions that can simulate maltreatment. Unrecognized cases of abuse may lead to insufficient child protection, whereas, on the other hand, over-diagnosis could be the cause of various problems for the family and their potentially accused members. Regarding child abuse, numerous cases of false diagnoses with undetected causes of bleeding are described in the scientific literature, but, specifically concerning leukemia in childhood, only very few case reports exist. Here, for the first time, we report a case of a 2-year-old boy who got hospitalized twice because of suspicious injuries and psychosocial conspicuities, in a family situation known for repeated endangerment of the child's well-being. After his first hospitalization with injuries typical for child abuse, but without paraclinical abnormalities, medical inspections were arranged periodically. The child was hospitalized with signs of repeated child abuse again five months later. During second admission, an acute lymphoblastic leukemia was revealed by intermittent laboratory examination, ordered due to new bruises with changes in morphology, identifiable as petechial hemorrhages. This case elucidates the discussion of known cases of leukemia in childhood associated with suspected child abuse in order to provide an overview of possible diseases mimicking maltreatment. To arrange necessary supportive examinations, a skillful interaction between pediatrician and forensic pathologist is crucial in the differentiation between accidental and non-accidental injury.

Tedizolid susceptibility in linezolid- and vancomycin-resistant Enterococcus faecium isolates.

Vancomycin-resistant enterococci (VRE) are of ever-increasing importance, most notably in high-risk patient populations. Therapy options are often limited for these isolates, and apart from tigecycline and daptomycin, oxazolidinone linezolid is frequently administered. The broad usage of linezolid, however, has driven the emergence of linezolid-resistant VRE strains (LR-VRE), further shortening therapeutic options. Second-generation oxazolidinone tedizolid has the advantage of being active against a specific subset of LR-VRE, i.e. isolates expressing the plasmid-encoded chloramphenicol-florfenicol resistance (cfr) gene. Here we tested tedizolid activity in a collection of 30 LR Enterococcus faecium VRE (MIC range 32-256 mg/l) isolated between 2012 and 2015 from clinical and screening specimens. By pulsed field gel electrophoresis (PFGE) isolates were assigned to 16 clonal lineages. In three cases, linezolid-susceptible progenitor isolates of LR-VRE were isolated, thus demonstrating the de-novo emergence of the linezolid-resistant phenotype. PCR did not detect cfr, cfr(B) or novel oxazolidinone resistance gene optrA in LR-VRE. All isolates, however, carried mutations within the 23S rDNA. Compared to linezolid, tedizolid MICs were lower in all isolates (MIC range 2-32 mg/l), but remained above the FDA tedizolid breakpoint for E. faecalis at 0.5 mg/l. Thus, related to the predominant resistance mechanism, tedizolid is of limited value for treatment of most LR-VRE and represents a therapeutic option only for a limited subset of isolates.

Latent class analysis of diagnostic tests for adenovirus, Bordetella pertussis and influenza virus infections in German adults with longer lasting coughs.

Laboratory tests in adult outpatients with longer lasting coughs to identify a potential causal pathogen are rarely performed, and there is no gold standard for these diagnostic tests. While the diagnostic validity of serological tests for pertussis is well established their potential contribution for diagnosing adenovirus and influenza virus A and B infections is unclear. A sentinel study into the population-based incidence of longer lasting coughs in adults was done in Rostock (former East Germany) and Krefeld (former West Germany). A total of 971 outpatients who consulted general practitioners or internists were included. Inclusion criteria were coughing for ⩾1 week and no chronic respiratory diseases. We evaluated the performance of polymerase chain reaction (PCR) as well as IgG and IgA serology, applying a latent class model for diagnosing infections with adenovirus, B. pertussis, and influenza virus A and B. The adult outpatients first sought medical attention when they had been coughing for a median of 3 weeks. In this situation, direct detection of infectious agents by PCR had a low sensitivity. Modelling showed that additional serological tests equally improved sensitivity and specificity for diagnosis for adenovirus, B. pertussis and influenza virus A and B infections. The combination of serology and PCR may improve the overall performance of diagnostic tests for B. pertussis and also for adenovirus, and influenza virus A and B infections.

New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor.

BACKGROUND: The influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients. METHODS: Data from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included. RESULTS: NODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(±1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (±2.67) years). CONCLUSION: NODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor.

Thymic stromal lymphopoietin deficiency attenuates experimental autoimmune encephalomyelitis.

In the present study we examined the role of thymic stromal lymphopoietin (TSLP) in experimental autoimmune encephalomyelitis (EAE). Here, we report that TSLP knock-out (KO) mice display a delayed onset of disease and an attenuated form of EAE. This delayed onset was accompanied by a reduced number of encephalitogenic T helper type 1 (Th1) cells in the central nervous system (CNS) of TSLP KO mice. In addition, CD4(+) and CD8(+) T cells from CNS of TSLP KO mice show a reduced activation status in comparison to wild-type mice. It is noteworthy that we could also show that lymph node cells from TSLP KO mice expanded less efficiently and that interleukin (IL)-6-, interferon (IFN)-γ and tumour necrosis factor (TNF)-α levels were reduced. Furthermore, CD3(+) T cells isolated in the preclinical phase from myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-immunized TSLP KO mice showed a reduced response after secondary exposure to MOG(35-55), indicating that differentiation of naive T cells into MOG(35-55)-specific effector and memory T cells was impaired in KO mice. The addition of recombinant TSLP enhanced T cell proliferation during MOG(35-55) restimulation, showing that T cells also respond directly to TSLP. In summary, these data demonstrate that expression of, and immune activation by, TSLP contributes significantly to the immunopathology of EAE.

Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012.

Despite more than 50 years of vaccination, pertussis is still an endemic disease, with regular epidemic outbreaks. With the exception of Poland, European countries have replaced whole-cell vaccines (WCVs) by acellular vaccines (ACVs) in the 1990s. Worldwide, antigenic divergence in vaccine antigens has been found between vaccine strains and circulating strains. In this work, 466 Bordetella pertussis isolates collected in the period 1998-2012 from 13 European countries were characterised by multi-locus antigen sequence typing (MAST) of the pertussis toxin promoter (ptxP) and of the genes coding for proteins used in the ACVs: pertussis toxin (Ptx), pertactin (Prn), type 2 fimbriae (Fim2) and type 3 fimbriae (Fim3). Isolates were further characterised by fimbrial serotyping, multi-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). The results showed a very similar B. pertussis population for 12 countries using ACVs, while Poland, which uses a WCV, was quite distinct, suggesting that ACVs and WCVs select for different B. pertussis populations. This study forms a baseline for future studies on the effect of vaccination programmes on B. pertussis populations.

Association between triglyceride and high-density lipoprotein cholesterol change following fibrate therapy.

BACKGROUND: Debate surrounding the role of fibrates has followed mixed outcomes from several randomised controlled trials. Subgroup analysis of even the negative trials reveals significant reduction in cardiovascular risk amongst patients with low HDL-C and high TG. We previously described factors associated with HDL-C change following fibrates. As fibrates influence both HDL-C and TG levels via their action on PPAR-α, we now wished to study TG change following fibrate therapy and any associations with baseline and change in HDL-C and TC levels. METHODS: Data was collected from case notes of patients started on fibrates (n=248) between 2002 and 2008 in the lipid clinics at Heart of England NHS Foundation Trust. Regression analyses were carried out to determine factors associated with changes in TG. RESULTS: Multiple regression analysis revealed that TG change was associated with pre-treatment TG (p<0.001) and TC levels (p=0.029). The association between TG change and pre-treatment TG remained significant when all factors including gender, concurrent statin treatment, diabetes and baseline HDL-C were entered into the regression model. Our previous study demonstrated significant post-fibrate HDL-C change in the group with baseline HDL-C values <1.0mmol/l. In our present study significant TG reduction was observed regardless of the baseline patient characteristics including HDL-C levels. CONCLUSIONS: The actions of fibrates are considered to be mediated via PPAR-α, but our data suggest that the effects on TG and HDL-C are different. Thus, the mechanisms mediating the changes of these lipids following fibrate treatment may vary.

Investigations into the emergence of pertactin-deficient Bordetella pertussis isolates in six European countries, 1996 to 2012.

Pathogen adaptation has been proposed to contribute to the resurgence of pertussis. A striking recent example is the emergence of isolates deficient in the vaccine component pertactin (Prn). This study explores the emergence of such Prn-deficient isolates in six European countries. During 2007 to 2009, 0/83 isolates from the Netherlands, 0/18 from the United Kingdom, 0/17 Finland, 0/23 Denmark, 4/99 Sweden and 5/20 from Norway of the isolates collected were Prn-deficient. In the Netherlands and Sweden, respectively 4/146 and 1/8 were observed in a later period (2010­12). The Prn-deficient isolates were genetically diverse and different mutations were found to inactivate the prn gene. These are indications that Prn-deficiency is subject to positive selective pressure. We hypothesise that the switch from whole cell to acellular pertussis vaccines has affected the balance between 'costs and benefits' of Prn production by Bordetella pertussis to the extent that isolates that do not produce Prn are able to expand. The absence of Prn-deficient isolates in some countries may point to ways to prevent or delay the spread of Prn-deficient strains. In order to substantiate this hypothesis, trends in the European B. pertussis population should be monitored continuously.

[Comparison of the OSDI and SPEED questionnaires for the evaluation of dry eye disease in clinical routine]. / Vergleich des OSDI- und SPEED-Fragbogens zur Evaluation des Sicca-Syndroms in der klinischen Praxis.

BACKGROUND: For the diagnosis of dry eye, taking an accurate medical history of the patient is critical. For this purpose the ocular surface disease index (OSDI) can be regarded as the established standard questionnaire but the standard patient evaluation of eye dryness (SPEED) questionnaire has recently been developed. The advantages of the SPEED questionnaire are the lower number of questions and easier interpretability. MATERIAL AND METHODS: In a retrospective analysis of 153 patients of our special clinic for dry eyes we performed a comparison of the SPEED with the established OSDI questionnaire regarding the evaluation of the severity of dry eye. In addition, we analyzed possible correlations with various objective parameters for classification of dry eye syndrome. RESULTS: There was a highly significant correlation between OSDI and SPEED values with a correlation coefficient of 0.47 (p < 0.001). In addition, significant correlations between OSDI values and the tear meniscus height (r = - 0.1374, p = 0.0226), Schirmer values (r = - 0.26, p < 0.0001) and lid margins parallel conjunctival folds (r = 0.1261, p = 0.034) were observed. The SPEED values showed a significant correlation with age (r = - 0.2106, p = 0.0107) and lipid layer thickness (r = - 0.159, p = 0.0081). DISCUSSION: The OSDI and SPEED questionnaires are both suitable for detecting the symptoms of dry eye; however the results of the questionnaires cannot be used interchangeably. While the SPEED levels seemed to correlate more with the parameters of evaporative dry eye, the OSDI values were more correlated with parameters of aqueous tear-deficient dry eye. However, a distinction between evaporative and aqueous tear-deficient dry eye is not possible based only on the results of the questionnaires.

Remediation of TENORM residues: risk communication in practice.

Despite several decades of studies on the risk assessment and risk perception of ionising radiation, risk management of radioactive materials remains a challenging issue. This is also true for wastes containing technologically enhanced naturally occurring radioactive materials. The present work focuses on the underlying reasons for communication problems between experts and affected members of the public. Exploring the case of a German remediation site with residual radioactive contamination in a residential area, the experts' as well as the residents' perspectives were studied by conducting qualitative interviews. Our results indicate a variety of reasons for communication problems on different levels of risk management and risk communication: the regulatory, the communicative and the moral levels. In the observed case, four salient causes for problems in risk communication and risk management emerged: the mismatch in understanding the residents' values, the issue of risk communication in an unforeseen situation, the problem of the regulatory gap between radiation protection and soil protection in regard to legacies with naturally occurring radioactive material in Germany, and the challenge of communicating a highly complex scientific issue to non-scientists. Moreover, one (at least partial) solution could be seen: the introduction of an external mediator. The results indicate that coordination of different health and environment protection disciplines-in this case radiation protection relating to soil protection-is possible and urgently needed. The opportunity to put, at least natural, radioactive material in line with other conventional industrial materials should be taken.

Endovascular aneurysm repair of abdominal aortic aneurysms: standards, technical options and advanced indications.

UNLABELLED: Since the introduction of endovascular aneurysm repair (EVAR) in 1991, the endovascular therapy with newest stent grafts has assumed a prominent role in the clinical management of abdominal aortic aneurysms (AAA) with a superior perioperative mortality of EVAR and an equivalent mid-term outcome, compared to open surgery. Newest techniques using chimney or periscope grafts and customized fenestrated and branched stent grafts allow the endovascular treatment of complex pararenal AAA. This article reviews EVAR in the treatment of AAA, evidence based results and advanced indication by newest interventional techniques and technical developments. KEY POINTS: • EVAR has become standard treatment of abdominal aortic aneurysm with equivalent results to open surgery.• Technical advancements and the introduction of newest stent grafts continually expand the indication of EVAR.• Chimney- and periscope grafts as well as custom-made prothesis systems allow endovascular treatment of complex para- and suprarenal aneurysms.