Old known and possible new biomarkers of ANCA-associated vasculitis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders involving severe, systemic, small-vessel vasculitis with short- and long term serious and life-threating complications. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. The pathogenesis of AAV is complex and unique, and despite the progress achieved in the last years, much has not to be learnt. Foremost, there is still no accurate marker enabling us to monitoring disease and guide therapy. Therefore, the disease management relays often on clinical judgment and follows a" trial and error approach". In the recent years, an increasing number of new molecules s have been explored and used for this purpose including genomics, B- and T-cell subpopulations, complement system factors, cytokines, metabolomics, biospectroscopy and components of our microbiome. The aim of this review is to discuss both the role of known historical and clinically established biomarkers of AAV, as well as to highlight potential new ones, which could be used for timely diagnosis and monitoring of this devastating disease, with the goal to improve the effectiveness and ameliorate the complications of its demanding therapy.

S1 guidelines "lumbar puncture and cerebrospinal fluid analysis" (abridged and translated version).

INTRODUCTION: Cerebrospinal fluid (CSF) analysis is important for detecting inflammation of the nervous system and the meninges, bleeding in the area of the subarachnoid space that may not be visualized by imaging, and the spread of malignant diseases to the CSF space. In the diagnosis and differential diagnosis of neurodegenerative diseases, the importance of CSF analysis is increasing. Measuring the opening pressure of CSF in idiopathic intracranial hypertension and at spinal tap in normal pressure hydrocephalus constitute diagnostic examination procedures with therapeutic benefits.Recommendations (most important 3-5 recommendations on a glimpse): The indications and contraindications must be checked before lumbar puncture (LP) is performed, and sampling CSF requires the consent of the patient.Puncture with an atraumatic needle is associated with a lower incidence of postpuncture discomfort. The frequency of postpuncture syndrome correlates inversely with age and body mass index, and it is more common in women and patients with a history of headache. The sharp needle is preferably used in older or obese patients, also in punctures expected to be difficult.In order to avoid repeating LP, a sufficient quantity of CSF (at least 10 ml) should be collected. The CSF sample and the serum sample taken at the same time should be sent to a specialized laboratory immediately so that the emergency and basic CSF analysis program can be carried out within 2 h.The indication for LP in anticoagulant therapy should always be decided on an individual basis. The risk of interrupting anticoagulant therapy must be weighed against the increased bleeding risk of LP with anticoagulant therapy.As a quality assurance measure in CSF analysis, it is recommended that all cytological, clinical-chemical, and microbiological findings are combined in an integrated summary report and evaluated by an expert in CSF analysis. CONCLUSIONS: In view of the importance and developments in CSF analysis, the S1 guideline "Lumbar puncture and cerebrospinal fluid analysis" was recently prepared by the German Society for CSF analysis and clinical neurochemistry (DGLN) and published in German in accordance with the guidelines of the AWMF (https://www.awmf.org). /uploads/tx_szleitlinien/030-141l_S1_Lumbalpunktion_und_Liquordiagnostik_2019-08.pdf). The present article is an abridged translation of the above cited guideline. The guideline has been jointly edited by the DGLN and DGN.

Early Signal of Emerging Nuclear Collectivity in Neutron-Rich

Radioactive ^{129}Sb, which can be treated as a proton plus semimagic ^{128}Sn core within the particle-core coupling scheme, was studied by Coulomb excitation. Reduced electric quadrupole transition probabilities, B(E2), for the 2^{+}⊗πg_{7/2} multiplet members and candidate πd_{5/2} state were measured. The results indicate that the total electric quadrupole strength of ^{129}Sb is a factor of 1.39(11) larger than the ^{128}Sn core, which is in stark contrast to the expectations of the empirically successful particle-core coupling scheme. Shell-model calculations performed with two different sets of nucleon-nucleon interactions suggest that this enhanced collectivity is due to constructive quadrupole coherence in the wave functions stemming from the proton-neutron residual interactions, where adding one nucleon to a core near a double-shell closure can have a pronounced effect. The enhanced electric quadrupole strength is an early signal of the emerging nuclear collectivity that becomes dominant away from the shell closure.

Generation of a zinc and rhodium containing metallomacrocycle by rearrangement of a six-coordinate precursor complex.

Two pentadentate N3,P2 ligands coordinate zinc(ii) by their N3 pocket. Four free phosphine donors allow the coordination of four AuCl moieties leading to a pentanuclear ZnAu4 complex. In contrast, the attempt to use the phosphines for chelating coordination of two Rh(CO)Cl units results in a well-organized rearrangement that ends up with the formation of a metallomacrocycle in high yields.

MCC950 blocks enhanced interleukin-1ß production in patients with NLRP3 low penetrance variants.

OBJECTIVE: To determine the role of the NLRP3 inflammasome by using the selective NLRP3 inhibitor MCC950 in patients with NLRP3 low penetrance variants and clinical symptoms suggestive for an autoinflammatory syndrome including central nervous system (CNS) involvement. METHODS: Nineteen symptomatic patients with low penetrance NLRP3 variants (Q703K n = 17, V198M n = 2) recruited between 2011 and 2017 were included in this monocentric study. A functional inflammasome activation assay was performed in patients in comparison to healthy controls (HC), including the determination of interleukin-1beta (IL-1ß), interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) secretion in the presence of the NLRP3 selective small-molecule inhibitor MCC950. Detailed clinical features were assessed and anti-IL-1 treatment response was determined. RESULTS: Peripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants displayed enhanced IL-1ß levels following inflammasome activation compared to HC. Furthermore, IL-1ß release was NLRP3-dependent as it was blocked by MCC950. The production of IL-6 and TNF-α was also increased in patients with low penetrance NLRP3 variants. Clinically, they presented with a heterogenous spectrum of neurological manifestations, while cranial nerve inflammation was the most common feature. Overall inflammasome activation did not correlate with disease severity. Eight of ten treated patients responded to anti IL-1 treatment, however a complete response was only documented in four patients. CONCLUSION: PBMC of several patients with NLRP3 low penetrance variants and CNS manifestation showed increased NLRP3-specific IL-1ß release upon stimulation and elevated NLRP3-independent IL-6 and TNF-α levels as those were not suppressed by MCC950. Our data suggest that beside the possible causal involvement of the NLRP3 inflammasome additional, yet unidentified genetic or environmental factors may contribute to the multi-organ inflammation in our patients and explain the partial response to IL-1 targeting therapies.

Immunophenotyping of cerebrospinal fluid cells in ischaemic stroke.

BACKGROUND AND PURPOSE: Post-ischaemic immune cell invasion into the brain is well characterized in animal stroke models and contributes to neuronal damage. Therefore, it represents a promising therapeutic target. Cerebrospinal fluid (CSF) is easily accessible and may reflect cellular events within the parenchyma. However, comprehensive studies on CSF immune cells in patients with stroke are lacking. METHODS: In a retrospective cohort study, we performed extensive immune-cell profiling in CSF and peripheral blood of patients with acute ischaemic stroke and healthy controls. In patients with stroke, infarct size was quantified on follow-up imaging. RESULTS: Overall, 90 patients with ischaemic stroke and 22 controls were included in our study. After stroke, the total protein was increased (537.3 vs. 353.2 mg/L, P = 0.008) and the mean total white cell count was slightly but non-significantly elevated (1.76 vs. 0.50 cells/µL, P = 0.059). Proportions of CSF lymphocytes, monocytes and granulocytes and their respective subsets did not differ between patients with stroke and controls. In addition, there were no associations between proportions of major leukocyte subsets in CSF and the time from symptom onset to CSF sampling, infarct size or infarct localization. CONCLUSIONS: Ischaemic stroke induces only a very slight increase of CSF immune cells without changes in the composition of immune cell subsets, thus indicating that parenchymal inflammation is not sufficiently reflected in the CSF. Our findings suggest that CSF is not a major invasion route for immune cells and that CSF cell analyses are not suitable as biomarkers to guide future immune therapies for stroke.

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. / Langzeit-Augmentationstherapie von Patienten mit Alpha-1-Antitrypsin-Mangel in der häuslichen Pflege.

BACKGROUND: Augmentation with human alpha-1 proteinase inhibitor is the only specific treatment for Alpha-1-Antitrypsin Deficiency (AATD), a rare genetic disease with symptoms of progressive COPD. OBJECTIVES: A prospective long-term exploration of outcomes during the "Alpha-1-Mobile" home care AAT augmentation program in seven advanced-stage patients. METHODS: Patients received weekly i. v. AAT augmentation and COPD therapy. Symptoms, lung function, health status, quality-of-life aspects, and safety were documented continuously. Outcomes during six years of home care augmentation therapy were observed and evaluated on an inter- and intraindividual basis. FEV1 profiles were compared to pre-program data. RESULTS: The seven patients had a mean age of 56.7 (40-68) years and had previously received augmentation for 8.8 (1-19) years. Compared to the three-year preprogram period, functional decline of FEV1 (ΔFEV1 0.47 L vs 0.17 L) slowed. Mean QoL scores showed seasonal fluctuations in the first three years of observation, and then stabilized. All blood samples tested exceeded the protective threshold of 50 mg/dL with a dose of 60 mg AAT/kg/week. Less than one exacerbation-related hospitalization occurred per patient-year. No adverse events of related to augmentation therapy were observed. CONCLUSIONS: Home care with i. v. augmentation therapy by medical professionals contributes to optimum care through consistent treatment and close health-status monitoring in our collective. Exacerbation-related hospitalizations were largely avoided. "Alpha-1-Mobile" was well accepted, practical, and safe.

[Chronic Disease Self-management Support for People with a Migrant Background: towards a Peer-led Group Program to Improve Equity in Health]. / Selbstmanagementförderung bei chronischer Krankheit für Menschen mit Migrationshintergrund ­ ein Gruppenkurs mit Peer-Ansatz als Beitrag zu gesundheitlicher Chancengerechtigkeit.

AIM: Limited health literacy and language skills are barriers for people with a migrant background (PMB) to access health information and healthcare services, in particular for those living with chronic conditions. During the introduction of a peer-led Stanford chronic disease self-management course in Switzerland, special interest in the program as well as motivation of PMB was observed. In response, we examined if the program can be implemented in German for people with limited language skills. METHODS: This explorative study is part of the evaluation study on introducing the adapted Stanford program in Switzerland and German-speaking Europe. Following the principles of Grounded Theory, semi-structured focus group and individual interviews were conducted with course participants, leaders and coordinators (n=30) and analyzed thematically. The focus was on the feasibility, satisfaction and course content. RESULTS: In principle, the program seems to have positive value for PMB, may work for them in German, have high relevance for everyday life and give an impetus for social integration. CONCLUSION: The need for and extent of modification of the program for PMB has to be further explored in order to make it more accessible for vulnerable groups.

Impact of Modular Total Absorption Spectrometer measurements of ß decay of fission products on the decay heat and reactor ν[over ¯]_{e} flux calculation.

We report the results of a ß-decay study of fission products ^{86}Br, ^{89}Kr, ^{89}Rb, ^{90gs}Rb, ^{90m}Rb, ^{90}Kr, ^{92}Rb, ^{139}Xe, and ^{142}Cs performed with the Modular Total Absorption Spectrometer (MTAS) and on-line mass-separated ion beams. These radioactivities were assessed by the Nuclear Energy Agency as having high priority for decay heat analysis during a nuclear fuel cycle. We observe a substantial increase in ß feeding to high excited states in all daughter isotopes in comparison to earlier data. This increases the average γ-ray energy emitted by the decay of fission fragments during the first 10 000 s after fission of ^{235}U and ^{239}Pu by approximately 2% and 1%, respectively, improving agreement between results of calculations and direct observations. New MTAS results reduce the reference reactor ν[over ¯]_{e} flux used to analyze reactor ν[over ¯]_{e} interaction with detector matter. The reduction determined by the ab initio method for the four nuclear fuel components, ^{235}U, ^{238}U, ^{239}Pu, and ^{241}Pu, amounts to 0.976, 0.986, 0.983, and 0.984, respectively.

Electromagnetic Moments of Radioactive

Radioactive ^{136}Te has two valence protons and two valence neutrons outside of the ^{132}Sn double shell closure, providing a simple laboratory for exploring the emergence of collectivity and nucleon-nucleon interactions. Coulomb excitation of ^{136}Te on a titanium target was utilized to determine an extensive set of electromagnetic moments for the three lowest-lying states, including B(E2;0_{1}^{+}→2_{1}^{+}), Q(2_{1}^{+}), and g(2_{1}^{+}). The results indicate that the first-excited state, 2_{1}^{+}, composed of the simple 2p⊕2n system, is prolate deformed, and its wave function is dominated by excited valence neutron configurations, but not to the extent previously suggested. It is demonstrated that extreme sensitivity of g(2_{1}^{+}) to the proton and neutron contributions to the wave function provides unique insight into the nature of emerging collectivity, and g(2_{1}^{+}) was used to differentiate among several state-of-the-art theoretical calculations. Our results are best described by the most recent shell model calculations.

Custom-made total ankle arthroplasty for the salvage of major talar bone loss.

AIMS: A failed total ankle arthroplasty (TAA) is often associated with much bone loss. As an alternative to arthrodesis, the surgeon may consider a custom-made talar component to compensate for the bone loss. Our aim in this study was to assess the functional and radiological outcome after the use of such a component at mid- to long-term follow-up. PATIENTS AND METHODS: A total of 12 patients (five women and seven men, mean age 53 years; 36 to77) with a failed TAA and a large talar defect underwent a revision procedure using a custom-made talar component. The design of the custom-made components was based on CT scans and standard radiographs, when compared with the contralateral ankle. After the anterior talocalcaneal joint was fused, the talar component was introduced and fixed to the body of the calcaneum. RESULTS: At a mean follow-up of 6.9 years (1 to 13), 11 ankles were stable with no radiological evidence of loosening. Only one was lost to follow-up. The mean arc of movement was 21° (10° to 35°). A total of nine patients (75%) were satisfied or very satisfied with the outcome, two (17%) were satisfied but with reservations and one (8%) was not satisfied. All but one patient had an improvement in the American Orthopaedic Foot and Ankle Society hindfoot score (p = 0.01). Just one patient developed deep infection, leading to arthrodesis. CONCLUSION: A custom-made talar component yielded satisfactory results with regard to function, stability and satisfaction. This should encourage the use of such components as an alternative to arthrodesis of the ankle in patients with a failed TAA. Cite this article: Bone Joint J 2017;99-B:231-6.

Optimal control of complex atomic quantum systems.

Quantum technologies will ultimately require manipulating many-body quantum systems with high precision. Cold atom experiments represent a stepping stone in that direction: a high degree of control has been achieved on systems of increasing complexity. However, this control is still sub-optimal. In many scenarios, achieving a fast transformation is crucial to fight against decoherence and imperfection effects. Optimal control theory is believed to be the ideal candidate to bridge the gap between early stage proof-of-principle demonstrations and experimental protocols suitable for practical applications. Indeed, it can engineer protocols at the quantum speed limit - the fastest achievable timescale of the transformation. Here, we demonstrate such potential by computing theoretically and verifying experimentally the optimal transformations in two very different interacting systems: the coherent manipulation of motional states of an atomic Bose-Einstein condensate and the crossing of a quantum phase transition in small systems of cold atoms in optical lattices. We also show that such processes are robust with respect to perturbations, including temperature and atom number fluctuations.

Decays of the Three Top Contributors to the Reactor ν[over ¯]_{e} High-Energy Spectrum,

We report total absorption spectroscopy measurements of ^{92}Rb, ^{96gs}Y, and ^{142}Cs ß decays, which are the most important contributors to the high energy ν[over ¯]_{e} spectral shape in nuclear reactors. These three ß decays contribute 43% of the ν[over ¯]_{e} flux near 5.5 MeV emitted by nuclear reactors. This ν[over ¯]_{e} energy is particularly interesting due to spectral features recently observed in several experiments including the Daya Bay, Double Chooz, and RENO Collaborations. Measurements were conducted at Oak Ridge National Laboratory by means of proton-induced fission of ^{238}U with on-line mass separation of fission fragments and the Modular Total Absorption Spectrometer. We observe a ß-decay pattern that is similar to recent measurements of ^{92}Rb, with a ground-state to ground-state ß feeding of 91(3)%. We verify the ^{96gs}Y ground-state to ground-state ß feeding of 95.5(20)%. Our measurements substantially modify the ß-decay feedings of ^{142}Cs, reducing the ß feeding to ^{142}Ba states below 2 MeV by 32% when compared with the latest evaluations. Our results increase the discrepancy between the observed and the expected reactor ν[over ¯]_{e} flux between 5 and 7 MeV, the maximum excess increases from ∼10% to ∼12%.

Evidence for Gamow-Teller Decay of

The ß-delayed neutron emission of ^{83,84}Ga isotopes was studied using the neutron time-of-flight technique. The measured neutron energy spectra showed emission from states at excitation energies high above the neutron separation energy and previously not observed in the ß decay of midmass nuclei. The large decay strength deduced from the observed intense neutron emission is a signature of Gamow-Teller transformation. This observation was interpreted as evidence for allowed ß decay to ^{78}Ni core-excited states in ^{83,84}Ge favored by shell effects. We developed shell model calculations in the proton fpg_{9/2} and neutron extended fpg_{9/2}+d_{5/2} valence space using realistic interactions that were used to understand measured ß-decay lifetimes. We conclude that enhanced, concentrated ß-decay strength for neutron-unbound states may be common for very neutron-rich nuclei. This leads to intense ß-delayed high-energy neutron and strong multineutron emission probabilities that in turn affect astrophysical nucleosynthesis models.

[Cytology of cerebrospinal fluid : Standards, importance and modern methods]. / Liquorzytologie : Standards, Stellenwert und moderne Methoden.

Cytology is an integral part of cerebrospinal fluid (CSF) analysis. It is relevant for the diagnostics and differential diagnosis of inflammatory, hemorrhagic and neoplastic central nervous system (CNS) processes. This article summarizes the recommended procedures and typical clinical patterns. In addition, modern immunocytochemical and flow cytometry methods for CSF cytology are presented. In particular, the diagnostic contribution and clinical relevance in several CNS conditions are discussed.

[Characteristics of neuromuscular scoliosis]. / Besonderheiten neuromuskulärer Skoliosen.

Usually, neuromuscular scolioses become clinically symptomatic relatively early and are rapidly progressive even after the end of growth. Without sufficient treatment they lead to a severe reduction of quality of life, to a loss of the ability of walking, standing or sitting as well as to an impairment of the cardiopulmonary system resulting in an increased mortality. Therefore, an intensive interdisciplinary treatment by physio- and ergotherapists, internists, pediatricians, orthotists, and orthopedists is indispensable. In contrast to idiopathic scoliosis the treatment of patients with neuromuscular scoliosis with orthosis is controversially discussed, whereas physiotherapy is established and essential to prevent contractures and to maintain the residual sensorimotor function.Frequently, the surgical treatment of the scoliosis is indicated. It should be noted that only long-segment posterior correction and fusion of the whole deformity leads to a significant improvement of the quality of life as well as to a prevention of a progression of the scoliosis and the development of junctional problems. The surgical intervention is usually performed before the end of growth. A prolonged delay of surgical intervention does not result in an increased height but only in a deformity progression and is therefore not justifiable. In early onset neuromuscular scolioses guided-growth implants are used to guarantee the adequat development. Because of the high complication rates, further optimization of these implant systems with regard to efficiency and safety have to be addressed in future research.

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Crystallization in Ising quantum magnets.

Dominating finite-range interactions in many-body systems can lead to intriguing self-ordered phases of matter. For quantum magnets, Ising models with power-law interactions are among the most elementary systems that support such phases. These models can be implemented by laser coupling ensembles of ultracold atoms to Rydberg states. Here, we report on the experimental preparation of crystalline ground states of such spin systems. We observe a magnetization staircase as a function of the system size and show directly the emergence of crystalline states with vanishing susceptibility. Our results demonstrate the precise control of Rydberg many-body systems and may enable future studies of phase transitions and quantum correlations in interacting quantum magnets.

Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population.

BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP.