High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

[DreKiP - an outpatient treatment program for children and adolescents with headache]. / DreKiP ­ ein ambulantes Therapieprogramm für Kinder und Jugendliche mit Kopfschmerzen.

Headaches are a frequent health problem among children and adolescents. The ocurrence of headaches and the resulting impairments in the quality of life and activities of daily living are modulated by biopsychosocial interactions, which necessitate a complex treatment program. The Dresden Childrens Headache Program (DreKiP) is a multidisciplinary therapy program consisting of eight modules for children and adolescents: education, stress relief, relaxation techniques, physical fitness, climbing therapy, art therapy and sensory training. In addition, there are six modules containing parallel workshops for parents. This outpatient program lasts 2-3 months and is performed parallel to the daily and school routine. Therapy groups consist of 6-8 patients in each age group. In total patients receive 15 h and the parents 7 h of therapy. Concomitant with the program, headache-associated data, such as headache frequency, medication use and school absence are documented. So far 32 children and adolescents in groups of 11, 14-15, 14-16, 17 and 17-18 years old completed the program. Of the 32 patients 19 presented with migraine and tension type headache, 6/32 with migraine and 7/32 with tension type headache only. The median number of headache days was 15 per month and 4 official school absence days per month. Preliminary results 6 months after the end of the therapy program showed reduced frequency of headaches in three quarters of our patients. The headache frequency was reduced from an initial median of 15 days per month to a median of 8 days per month after the program. The multidisciplinary program DreKiP improves the use of therapeutic means in children and adolescents with primary headaches. Children and adolescents with headache-related impairment in activities of daily life in school and leisure times constitute the target group of this therapy.

Correlated Electron Dynamics at Surfaces Investigated via He

The neutralization of a single He^{2+} ion near a Ir surface leads to the emission of an electron pair. Via coincidence spectroscopy we give evidence that a sizable amount of these electron pairs originate from a correlated single step neutralization of the ion involving a total of four electrons from the metal. These correlated electron pairs cannot be explained in the common picture of two consecutive and independent neutralization steps. We infer a characteristic time scale for the correlated electron dynamics in the metal of 40-400 as.

Observation and Structure Determination of an Oxide Quasicrystal Approximant.

We report on the first observation of an approximant structure to the recently discovered two-dimensional oxide quasicrystal. Using scanning tunneling microscopy, low-energy electron diffraction, and surface x-ray diffraction in combination with ab initio calculations, the atomic structure and the bonding scheme are determined. The oxide approximant follows a 3^{2}.4.3.4 Archimedean tiling. Ti atoms reside at the corners of each tiling element and are threefold coordinated to oxygen atoms. Ba atoms separate the TiO_{3} clusters, leading to a fundamental edge length of the tiling 6.7 Å.

Core-resonant double photoemission from palladium films.

We studied the core-resonant double photoemission process from palladium films with linearly polarized synchrotron radiation. We excited either the 3d or 4p core level and focused on the Auger transitions which leave two holes in the valence band. We find that the two-dimensional energy distributions are markedly different for the 3d and 4p decay. The 3d decay can be understood by a sequential emission of the two electrons while the 4p decay proceeds in a single step. Despite the large differences in the two-dimensional energy spectra we find the shape of the energy sum spectra rather similar. For the description of the 4p decay we propose a model which uses available single electron spectra, but suggest an alternative interpretation of these data. With this we are able to explain the range over which the available energy is shared. Key assumptions of the model are verified by our experiments on the 3d decay.

The LVV Auger line shape of sulfur on copper studied by Auger photoelectron coincidence spectroscopy.

We have studied the line shapes of Cu(0 0 1)-p (2 × 2)S L2VV and L3VV Auger decay by means of Auger photoelectron coincidence spectroscopy. Measuring the LVV Auger spectrum in coincidence with S 2p1/2 and 2p3/2 photoelectrons respectively, we have been able to separate the two overlapping Auger spectra and determine their intrinsic line shapes. The two Auger transitions, though shifted in energy, display an identical line shape whose main features can be qualitatively understood considering a single particle approximation but are better described within a Cini-Sawatzky (CS) approach. Comparison between the experimental and the CS calculated spectra confirms that a substantial part of the Auger lines (∼20%) can be ascribed to decay events accompanied by the excitation of one additional electron-hole pair in the valence band. For the first time, the locality of the Auger process combined with the surface sensitivity of the APECS technique and its ability to separate overlapping structures are used to study Auger transitions taking place at the the surface states of a S/noble-metal interface.

Energy relations of positron-electron pairs emitted from surfaces.

The impact of a primary positron onto a surface may lead to the emission of a correlated positron-electron pair. By means of a lab-based positron beam we studied this pair emission from various surfaces. We analyzed the energy spectra in a symmetric emission geometry. We found that the available energy is shared in an unequal manner among the partners. On average the positron carries a larger fraction of the available energy. The unequal energy sharing is a consequence of positron and electron being distinguishable particles. We provide a model which explains the experimental findings.

Dynamic screening probed by core-resonant double photoemission from surfaces.

The universal response of a sudden created core hole, predicted to occur on an attosecond (10(-18) s) time scale, lacks an experimental demonstration. With a two-dimensional coincidence spectrometer, we demonstrate an extensive energy sharing between the Ag 4p photoelectron and the N2,3VV Auger electron exceeding 10 eV. This energy width provides access to the time scale of the emission process. This is the fingerprint of the dynamic fluctuation process 4p(-1)⇌4d(-2)4f. The shakeup induced interband transitions from the Ag(100) surface are also identified by comparing the coincidence spectrum with the M4,5VV Auger transitions.

Exploring highly correlated materials via electron pair emission: the case of NiO/Ag(100).

Metal oxides like NiO are usually termed 'highly correlated', because the material properties are decisively determined by the electron-electron interaction. This makes them interesting candidates for electron pair spectroscopy which is particularly sensitive to the electron correlation. We have prepared ultrathin NiO/Ag(100) films and studied the electron pair emission upon electron impact. Compared to the metal substrate we observe an increase of the coincidence intensity by a factor of 8 for NiO. Thickness dependent measurements prove that this enhancement is an intrinsic effect rather than due to a mean free path increase of the oxide. The Néel temperature T(N) of NiO films displays a thickness dependence which allows us to tune T(N). We performed temperature dependent measurements and observed no temperature dependence of the coincidence spectra. This proves that the electron pair emission probes the local correlation rather than long range order. An enhanced coincidence intensity was also found for other oxide phases compared to their corresponding metal phases.

[Living and dying in community based housing for people with dementia. An exploratory qualitative study]. / Leben und Sterben in Wohngemeinschaften für Menschen mit Demenz. Eine explorative qualitative Studie.

Community based housing for people with dementia is gaining importance. In co-operation between the people concerned, their relatives, professionals and volunteers, person-centred care, nursing and guidance can be realised within small units. Questions regarding end of life, dying, grief and the role of palliative care form the basis of the exploratory qualitative study presented here. Coping with end of life, ethical decisions and the relevance of hospice and palliative care in the field are highlighted. The results of the study show that "shared flats for people with dementia" are good places for death and dying. Close relationships, good communication with relatives and highly motivated professionals can be regarded as powerful resources. So far only few co-operations between hospice and palliative care exist. Areas of improvement encompass clinical issues and coping with bereavement.

Spin-resolved mapping of spin contribution to exchange-correlation holes.

By means of spin-polarized electron coincidence spectroscopy we explore the fundamental issue of spin-resolved contributions to the exchange-correlation hole in many-electron systems. We present a joint experimental and theoretical study of correlated electron pair emission from a ferromagnetic Fe(001) surface induced by spin-polarized low-energy electrons. We demonstrate that the contribution to the exchange-correlation hole due to exchange is more extended than the contribution due to the screened Coulomb interaction.

Electron pair emission from a W(001) surface: photon versus electron excitation.

The electron pair emission from a W(001) surface was studied using a coincidence time-of-flight spectrometer. The aim of this study was to compare the pair emission upon electron impact and upon photon absorption. The energy distributions are markedly different for these two experiments. From this we conclude that the photon-stimulated pair emission carries a significant contribution from a double photoemission process, while the process of first creating a photoelectron, which in a subsequent collision leads to pair emission, is of less importance.

Correlation effects in two electron photoemission.

Many-body effects in solids are ultimately related to the correlation among electrons, which can be probed by double photoelectron emission. We have investigated the electron pair emission from a Cu(111) surface upon photon absorption. We are able to observe for the first time the full extension and shape of a depletion zone around the fixed emission direction of one electron. It has an angular extension of approximately 1.2 rad, which is independent of the electron energy.

Mapping out electron-electron interactions at surfaces.

Using a high resolution coincidence technique, we measured for the first time the angular and energy correlation of an electron pair emitted from the valence band of a single crystal upon the impact of an electron with a specified momentum. We observe a hole in the measured two-particle correlation function when the two excited electrons have comparable momentum vectors, a fact traced back to exchange and repulsion among the electrons. We find the hole is not isotropic, has a finite extension, and is strongly suppressed when decoherence is operating.

Coulomb dissociation of 8B and the low-energy cross section of the 7Be(p,gamma)8B solar fusion reaction.

An exclusive measurement of the Coulomb breakup of 8B into 7Be+p at 254A MeV allowed the study of the angular correlations of the breakup particles. These correlations demonstrate clearly that E1 multipolarity dominates and that E2 multipolarity can be neglected. By using a simple single-particle model for 8B and treating the breakup in first-order perturbation theory, we extract a zero-energy S factor of S17(0)=18.6+/-1.2+/-1.0 eV b, where the first error is experimental and the second one reflects the theoretical uncertainty in the extrapolation.

T cell reactivity against the SmD1(83-119) C terminal peptide in patients with systemic lupus erythematosus.

BACKGROUND: The SmD1(83-119) peptide is a major target of the B cell response in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To investigate the T cell response directed against this peptide, its disease specificity, and possible impact on SLE pathogenesis. METHODS: Peripheral blood mononuclear cells derived from 28 patients with SLE and 29 healthy and disease controls were stimulated by the SmD1(83-119) and the recombinant (r)SmD1 protein, and [3H]thymidine incorporation was measured. Patients with SLE were simultaneously tested for autoantibodies, disease activity, clinical symptoms, and medical treatments. RESULTS: T cell reactivity against the SmD1(83-119) peptide was detected in 11/28 (39%) patients with SLE and against the rSmD1 protein in 10/28 (36%) patients. In contrast, only 2/29 (7%) controls exhibited SmD1 reactivity. An analysis of proliferation kinetics showed that SmD1 reactive T cells are activated in vivo, as additionally confirmed by cytometric analysis. Addition of mammalian dsDNA to rSmD1 enhanced the rSmD1-specific T cell response. SmD1(83-119)-specific T cell reactivity was significantly more common in patients with cardiac and pulmonary symptoms. No correlation between T and B cell responses and disease activity was seen. CONCLUSION: SmD1(83-119) is a major T cell epitope of SmD1, commonly recognised by T cells from patients with SLE and much less commonly found by healthy or disease controls. This strong T cell reactivity as well as the high frequency and specificity of anti-SmD1(83-119) antibodies in SLE suggest a possible role in SLE pathogenesis, at least in a subset of patients.

Development and validation of a semiautomatic image analysis system for measuring skin desquamation with D-Squames.

BACKGROUND: D-Squames, have gained wide acceptance for assessing skin desquamation. The amount of corneocytes adhering to D-Squames can be assessed visually by trained observers or by computerized image analysis. Different image analysis algorythms for the evaluation of D-Squames have been published but have not been compared with each other. It was our aim to develop an image analysis system that does not require an expensive image analysis programming tool but should be optimized for routine tasks of analysing large numbers of samples. A second objective of this study was to compare two published image analysis algorythms and visual grading. MATERIAL AND METHODS: The hardware components of the system are a CCD camera connected to a frame grabber card and a light box equipped with fluorescent tubes on two sides that provide a relatively cool, diffuse and even illumination of the sample. The following features were included into the software: generation and identification of bar codes for sample identification; semiautomatic recognition of ROI (region of interest), integration of study design into the analysing process, rapid calculation of desquamation index (DI: integration of the per cent area covered by scales and their thickness distribution) and/or scaling index (SI: distribution of grey values), data storage and export for further analysis. In a first step the system was validated by examining D-Squames covering a wide range of desquamation, by examining different ROI shapes (circle and square), by performing repeat measurements with different positions of the samples and by repeat measurements after re-callibrating the system. In a second step the effect of treatment with different moisturizers was evaluated by the two image analysis parameters DI and SI and compared with hydration measurements (Corneometer). RESULTS: The shape of the ROI showed no influence on the results (variability < 5%). Reproducibility of measurements was satisfactory (COV CDI): 1.7%, COV (SI): 2.6%). There was a good correlation between image analysis results and visual evaluation (means of 3 technicians) (r = 0.986) as well as between the two different image analysis parameters DI and SI (r = 0.971). In the clinical study moisturizer treatment resulted in variable reduction of desquamation that was closely correlated with increase in stratum corneum hydration (r = 0.97). CONCLUSION: Analysing D-Squames with the image analysis system proved to be reproducible, independent of the shape of ROI, cost effective and fast and easy to operate. It has shown to be a suitable and reliable method for the objective determination of desquamation levels.

The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis.

OBJECTIVE: The ubiquitously expressed intracellular protein formerly designated p68 has been identified as autoantigen at both the antibody and the T cell level in rheumatoid arthritis (RA). METHODS: We used 2 independent approaches, Edman degradation and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, to characterize p68, and we compared its features with those of the endoplasmic reticulum stress protein BiP. RESULTS: In synovial sections from RA patients, BiP was highly overexpressed as compared with control sections. Under in vitro stress conditions, BiP was found to translocate to the nucleus and the cell surface. BiP-specific autoantibodies were present in 63% of 400 RA patients, in 7% of 200 patients with other rheumatic diseases, and in none of the healthy subjects. Thus, BiP-specific autoantibodies represent a new diagnostic marker in RA. Furthermore, we found that BiP-specific T cell reactivity was altered in RA. In healthy individuals and patients with other rheumatic diseases, BiP-reactive T cells were undetectable. In RA, overt T cell reactivity to BiP was observed or could be induced by specifically blocking antigen presentation to potentially regulatory T cells. CONCLUSION: Since overexpression of BiP has been shown to decrease the sensitivity of cells to killing by cytotoxic T cells, BiP overexpression and BiP-specific autoimmunity may be involved in the pathogenesis of RA.

p205 is a major target of autoreactive T cells in rheumatoid arthritis.

OBJECTIVE: The p205 autoantigen and interleukin-2 (IL-2) function synergistically to stimulate T lymphocytes from patients with rheumatoid arthritis (RA), and a p205-derived amino acid sequence is identical to an immunoglobulin sequence located within a domain that is reactive with rheumatoid factors (RF). This study was conducted to analyze in detail the T cell immune response against p205 and to investigate whether immunity to p205 may play a role in T cell-mediated immunopathology in active RA. METHODS: Cibachron blue, protein A-Sepharose, and gel filtration on Sephacryl were used successively to enrich p205 from synovial fluid (SF). T lymphocytes from RA patients were isolated from the peripheral blood (PB), lymph nodes, and SF, and p205 and peptides derived from known sequences were assessed by T cell proliferation assays in the presence of IL-2. RESULTS: P205-specific proliferation of T cells was observed in PB as well as in SF. When p205 was isolated from RA SF, proliferation of RA T cells peaked on day 3. With p205 purified from SF from trauma patients, there was a significant shift of the maximum T cell proliferation to day 8. T cells were of CD4 or CD8 phenotype, and B cells did not proliferate to a significant degree. The T cell response to p205 was always higher for SF mononuclear cells (SFMC) compared with PBMC (P < 0.001). In 1 RA patient who underwent repeated leukapheresis, this led to a reproducible decline in p205-specific T cell proliferation to control levels. PB T cells specifically proliferating in response to p205 were detected in 20 of 32 RA patients (63%). Of 26 patients with other inflammatory rheumatic diseases, only 1 showed a minor response to p205, while normal donors did not demonstrate a significant T cell proliferation. A synthetic p205-derived peptide, with an amino acid sequence identical to an immunoglobulin sequence located in the area where RF binds, was reactive with T cells from RA patients. CONCLUSION: P205 appears to be a major target of autoreactive T cells in RA. P205-specific T cells are primed and more abundant at the site of inflammation. As a T cell target in RA, p205 may well be an antigen involved in the initiation of RF production.