[Rheumatology centers according to the regulations of the Federal Joint Committee]. / Rheumatologische Zentren entsprechend den Regelungen des Gemeinsamen Bundesausschusses.

With the Nursing Staff Strengthening Act (Pflegepersonal-Stärkungs-Gesetz), the legislator delegated the specification of the special tasks of centers and focal points to the Federal Joint Committee (G-BA). Due to extensive preliminary work it was already possible to agree on quality requirements and special tasks for rheumatology centers and centers for pediatric and adolescent rheumatology in the first version of the G­BA regulations. Since publication in the Federal Gazette (Bundesanzeiger) on 12 March 2020, rheumatology centers have been able to negotiate surcharges for their special tasks if they have been designated accordingly by the state authorities responsible for hospital planning. So far, 14 rheumatological centers have been designated. Many patients continue to be treated in healthcare structures that are not specialized in acute inpatient rheumatological care. In addition to the additional remuneration, the designation as a rheumatology center can also contribute to patients becoming even more aware of the healthcare structures that are specialized for them. Acute inpatient rheumatology has several specializations. Some clinics have specialized in the multimodal treatment of chronic rheumatism patients and have gained a high level of expertise in this field. Many of these highly specialized clinics have so far been denied recognition as a center because the regulations of the G­BA require the provision of further specialist departments at the same location. While for a large number of medical specializations the establishment at a maximum care hospital is likely to make sense, the specialist clinics focusing on the multimodal treatment of chronic rheumatism patients offer the possibility of strengthening rural areas.

[Patient-reported outcomes in German vasculitis patients-Data from the KOBRA quality project]. / Patient-reported-Outcomes bei Vaskulitispatienten in Deutschland ­ Daten aus dem KOBRA-Qualitätsprojekt.

BACKGROUND/OBJECTIVES: Current data on the care of patients with vasculitis in Germany are scarce. Patient-reported outcome (PRO) questionnaires can capture aspects of the disease that escape conventional scores for disease activity, remission, and damage. For this reason, the Association of Rheumatological Acute Care Clinics (VRA) initiated a data analysis as part of the KOBRA quality project, the results of which are presented here. PATIENTS AND METHODS: Patients with vasculitis of vessels of any size or with polymyalgia rheumatica were included. The prospective survey included data on demographics, disease, pain, treatment, follow-up and satisfaction at the time of inpatient admission, discharge and follow-up after 2.5 months. All patients completed the AAV-PRO and EQ-5D-3L questionnaires on admission and follow-up. RESULTS: In this study 420 patients were recruited and follow-up data were available from 302. On average, improvements were documented in all 5 dimensions of the EQ-5D, with the strongest effects in self-care and coping with activities of daily living. In the AAV-PRO, highly significant differences were seen in the domains systemic symptoms and physical functioning. Satisfaction with medical and nursing treatment was very high and did not correlate with pain level or with the AAV-PRO measures. DISCUSSION: Under zreatment patient-reported outcomes improve at least partially in vasculitis patients. Satisfaction with medical treatment quality is independent of these outcomes.

Stochastic Thermodynamics of a Finite Quantum System Coupled to Two Heat Baths.

We consider a situation where an N-level system (NLS) is coupled successively to two heat baths with different temperatures without being necessarily thermalized and approaches a steady state. For this situation we apply a general Jarzynski-type equation and conclude that heat and entropy is flowing from the hot bath to the cold one. The Clausius relation between increase of entropy and transfer of heat divided by a suitable temperature assumes the form of two inequalities. Our approach is illustrated by an analytical example. For the linear regime, i.e., for small temperature differences between the two heat baths, we derive an expression for the heat conduction coefficient.

[Rheumatologic inpatient treatment-more than a complex treatment : Data reflecting services and structures]. / Akutstationäre Rheumatologie ­ mehr als eine Komplexbehandlung : Versorgungsdaten und -strukturen.

To review and be prepared for upcoming reforms, data from the InEK (Institut für das Entgeltsystem im Krankenhaus, institute for remuneration in hospitals) data browser and the structured quality reports for inpatient rheumatologic treatment were evaluated. Rheumatologic treatment is very diversified, both in terms of diagnoses and structures. Different specializations can be identified. Rheumatologic complex treatment (RCT) is just one of these and is performed on average in just over 10% of cases. In 2020, cases for selected rheumatological diagnoses decreased by more than 20% compared to 2019. For RCT, the decline was even more pronounced with more than 30%. Evidence of higher disease severity could not be found in the available data. It remains to be seen whether the pre-Corona caseload will be regained in the coming years. In all, 146 organizational departments with more than 20 principal diagnoses of rheumatoid arthritis (RA) were identified in 2019. Forty-seven (32%) of these coded RCT more than ten times, and 29 (20%) more than one hundred times. All 23 departments with more than 300 principle diagnoses of RA are members of the Association of Rheumatological Acute Care Hospitals (Verband rheumatologischer Akutkliniken, VRA), 15 of which participated in the KOBRA quality project and carry the VRA seal of approval. Of the 116 internal medicine departments, only 55 (47%) use a specific specialty code for a rheumatology department according to Article 301 SGB V (social insurance code). Information on specialist staffing was partly contradictory. How many cases with inflammatory rheumatic diseases are treated in specialized departments cannot be answered with the available data. Nevertheless, the available data can be used for specialist, structural, and organizational developments in acute inpatient rheumatology.

[Publicity campaign rheuma2025 of the Union for Rheumatology]. / Öffentlichkeitskampagne "rheuma2025" des Bündnisses für Rheumatologie.

The publicity campaign "rheuma2025", initiated by the Union for Rheumatology, aims at improvement of patient-centered care. For this the number of positions for trainees in rheumatology needs to increase to a level which matches the public needs. Students in medical school must have even more interest for the discipline and they must be recruited. Regulatory constraints in the approval by the authorities for opening a private rheumatology practice must become much more flexible. The possibilities for in-patient acute care of patients in specialized hospitals have to be strengthened. Finally, the public image of rheumatology per se must be sharpened. To achieve these goals a homepage for the campaign was created ( https://rheuma2025.de ), which provides a toolkit of items for the public, for physicians and students. Various media channels for rheuma2025 were established with specific contents for each target group.

Spatiotemporal Resolution of Conformational Changes in Biomolecules by Combining Pulsed Electron-Electron Double Resonance Spectroscopy with Microsecond Freeze-Hyperquenching.

The function of proteins is linked to their conformations that can be resolved with several high-resolution methods. However, only a few methods can provide the temporal order of intermediates and conformational changes, with each having its limitations. Here, we combine pulsed electron-electron double resonance spectroscopy with a microsecond freeze-hyperquenching setup to achieve spatiotemporal resolution in the angstrom range and lower microsecond time scale. We show that the conformational change of the Cα-helix in the cyclic nucleotide-binding domain of the Mesorhizobium loti potassium channel occurs within about 150 µs and can be resolved with angstrom precision. Thus, this approach holds great promise for obtaining 4D landscapes of conformational changes in biomolecules.

[Perioprocedural mortality after ICD implantation]. / Peripoperative Mortalität nach ICD-Implantation.

BACKGROUND: Implantable cardioverter defibrillators (ICD) represent an established treatment in preventing sudden cardiac death in patients with indications for primary or secondary prophylaxis. As for all complex surgical procedures there remains a risk for the occurrence of complications including death also for ICD implantation. The aim of the present study was to analyze the procedure-related mortality in patients after ICD implantation using the data from the obligatory quality assurance program in North-Rhine/Westphalia. METHODS: Data of all 18,625 patients from the quality assurance datasets who underwent ICD implantation in the years 2010-2012 were analyzed. RESULTS: During the in-hospital stay 118 patients (0.6%) died after ICD implantation. Patients > 80 years old had a higher mortality (1.9% vs. 0.5% in patients < 80 years old, p < 0.001) as well as women (0.95% vs. 0.54% in men, p = 0.004) and patients with higher New York Heart Association (NYHA) class (0.3% for NYHA II, 0.7% for NYHA III, 3.4% for NYHA IV, p < 0.001 for all comparisons). The presence of diabetes mellitus (23% of the collective) did not influence the perioperative mortality, whereas renal failure requiring dialysis showed a significantly increased mortality (p < 0.001 compared to patients with creatinine ≤ 1.5 mg/dl and p = 0.002 for patients with creatinine > 1.5 mg/dl not requiring dialysis). Patients with indications for ICD secondary prophylaxis had a significantly higher mortality (1.2% vs. 0.4%, p < 0.001), which increased from 0.6% to 3.7% (p < 0.001) with the occurrence of complications. CONCLUSION: The procedure-related mortality after ICD implantation is increased in patients over 80 years of age, higher NYHA class, patients requiring dialysis, in secondary prevention indications and after the occurrence of perioperative complications.

Lipid Dynamics in Diisobutylene-Maleic Acid (DIBMA) Lipid Particles in Presence of Sensory Rhodopsin II.

Amphiphilic diisobutylene/maleic acid (DIBMA) copolymers extract lipid-encased membrane proteins from lipid bilayers in a detergent-free manner, yielding nanosized, discoidal DIBMA lipid particles (DIBMALPs). Depending on the DIBMA/lipid ratio, the size of DIBMALPs can be broadly varied which makes them suitable for the incorporation of proteins of different sizes. Here, we examine the influence of the DIBMALP sizes and the presence of protein on the dynamics of encased lipids. As shown by a set of biophysical methods, the stability of DIBMALPs remains unaffected at different DIBMA/lipid ratios. Coarse-grained molecular dynamics simulations confirm the formation of viable DIBMALPs with an overall size of up to 35 nm. Electron paramagnetic resonance spectroscopy of nitroxides located at the 5th, 12th or 16th carbon atom positions in phosphatidylcholine-based spin labels reveals that the dynamics of enclosed lipids are not altered by the DIBMALP size. The presence of the membrane protein sensory rhodopsin II from Natronomonas pharaonis (NpSRII) results in a slight increase in the lipid dynamics compared to empty DIBMALPs. The light-induced photocycle shows full functionality of DIBMALPs-embedded NpSRII and a significant effect of the protein-to-lipid ratio during preparation on the NpSRII dynamics. This study indicates a possible expansion of the applicability of the DIBMALP technology on studies of membrane protein-protein interaction and oligomerization in a constraining environment.

Conditional Action and Imperfect Erasure of Qubits.

We consider state changes in quantum theory due to "conditional action" and relate these to the discussion of entropy decrease due to interventions of "intelligent beings" and the principles of Szilard and Landauer/Bennett. The mathematical theory of conditional actions is a special case of the theory of "instruments", which describes changes of state due to general measurements and will therefore be briefly outlined in the present paper. As a detailed example, we consider the imperfect erasure of a qubit that can also be viewed as a conditional action and will be realized by the coupling of a spin to another small spin system in its ground state.

In cell Gd3+-based site-directed spin labeling and EPR spectroscopy of eGFP.

Label-based functional studies of biomolecules in their native environment require labeling reactions inside living cells. In cell spin labeling using alkyne-azide click chemistry with a Gd3+-DOTAM-azide complex is shown to provide high spin label stability and narrow EPR lines for EPR spectroscopic detection of a spin labeled protein in living cells at ambient temperatures.

Styrene/Maleic Acid Copolymers Form SMALPs by Pulling Lipid Patches out of the Lipid Bilayer.

Amphiphilic copolymers composed of styrene and maleic acid (SMA) monomers caused a major methodical breakthrough in the study of membrane proteins. They were found to directly release phospholipids and membrane proteins both from artificial and natural lipid bilayers, yielding stable water-soluble discoidal SMA/lipid particles (SMALPs) of uniform size. Although many empirical studies indicate the great potency of SMALPs for membrane protein research, the mechanisms of their formation remain obscure. It is unknown which factors account for the very assembly of SMALPs and govern their uniform size. We have developed a coarse-grained (CG) molecular model of SMA copolymers based on the MARTINI CG force field and used it to probe the behavior of SMA copolymers with varying composition/charge/concentration in solution as well as their interaction with lipid membranes. First, we found that SMA copolymers tend to aggregate in solution into clusters, which could account for the uniform size of SMALPs. Next, molecular dynamics (MD) simulations showed that periodic SMA copolymers with styrene/maleic acid ratios of 2:1 ([SSM] n) and 3:1 ([SSSM] n) differently interacted with lipid bilayers. While clusters of 2:1 SMA copolymers induced membrane poration, the clusters of 3:1 SMA copolymers extracted lipid patches from the membrane yielding SMALP-like structures. Extraction of lipid patches was also observed when we simulated the behavior of 3:1 copolymers with varying lengths and statistical distribution of styrene and MA units. Analysis of MD simulation trajectories and comparison with experimental data indicate that the formation of SMALPs requires copolymer molecules with a sufficient number of units made of more than two sequential styrene monomers.

Relationship of Catalysis and Active Site Loop Dynamics in the (ßα)8-Barrel Enzyme Indole-3-glycerol Phosphate Synthase.

It is important to understand how the catalytic activity of enzymes is related to their conformational flexibility. We have studied this activity-flexibility correlation using the example of indole-3-glycerol phosphate synthase from Sulfolobus solfataricus (ssIGPS), which catalyzes the fifth step in the biosynthesis of tryptophan. ssIGPS is a thermostable representative of enzymes with the frequently encountered and catalytically versatile (ßα)8-barrel fold. Four variants of ssIGPS with increased catalytic turnover numbers were analyzed by transient kinetics at 25 °C, and wild-type ssIGPS was likewise analyzed both at 25 °C and at 60 °C. Global fitting with a minimal three-step model provided the individual rate constants for substrate binding, chemical transformation, and product release. The results showed that in both cases, namely, the application of activating mutations and temperature increase, the net increase in the catalytic turnover number is afforded by acceleration of the product release rate relative to the chemical transformation steps. Measurements of the solvent viscosity effect at 25 °C versus 60 °C confirmed this change in the rate-determining step with temperature, which is in accordance with a kink in the Arrhenius diagram of ssIGPS at ∼40 °C. When rotational diffusion rates of electron paramagnetic spin-labels attached to active site loop ß1α1 are plotted in the form of an Arrhenius diagram, kinks are observed at the same temperature. These findings, together with molecular dynamics simulations, demonstrate that a different degree of loop mobility correlates with different rate-limiting steps in the catalytic mechanism of ssIGPS.

Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study.

Neutralizing autoantibodies against factor VIII (FVIII), also called FVIII inhibitors, are the cause of acquired hemophilia A (AHA). They are quantified in the Bethesda assay or Nijmegen-modified Bethesda assay by their ability to neutralize FVIII in normal human plasma. However, FVIII inhibitors do not represent the whole spectrum of anti-FVIII autoantibodies. Here, we studied isotypes, immunoglobulin G subclasses, and apparent affinities of anti-FVIII autoantibodies to assess their prognostic value for the outcome in AHA. We analyzed baseline samples from patients enrolled in the prospective GTH-AH 01/2010 study. Our data suggest that anti-FVIII immunoglobulin A (IgA) autoantibodies are predictors of poor outcome in AHA. Anti-FVIII IgA-positive patients achieved partial remission similar to anti-FVIII IgA-negative patients but had a higher risk of subsequent recurrence. Consequently, IgA-positive patients achieved complete remission less frequently (adjusted hazard ratio [aHR], 0.35; 95% confidence interval [CI], 0.18-0.68; P < .01) and had a higher risk of death (aHR, 2.62; 95% CI, 1.11-6.22; P < .05). Anti-FVIII IgA was the strongest negative predictor of recurrence-free survival after achieving partial remission and remained significant after adjustment for baseline demographic and clinical characteristics. In conclusion, anti-FVIII IgA represents a potential novel biomarker that could be useful to predict prognosis and tailor immunosuppressive treatment of AHA.

The nuclear F-actin interactome of Xenopus oocytes reveals an actin-bundling kinesin that is essential for meiotic cytokinesis.

Nuclei of Xenopus laevis oocytes grow 100 000-fold larger in volume than a typical somatic nucleus and require an unusual intranuclear F-actin scaffold for mechanical stability. We now developed a method for mapping F-actin interactomes and identified a comprehensive set of F-actin binders from the oocyte nuclei. Unexpectedly, the most prominent interactor was a novel kinesin termed NabKin (Nuclear and meiotic actin-bundling Kinesin). NabKin not only binds microtubules but also F-actin structures, such as the intranuclear actin bundles in prophase and the contractile actomyosin ring during cytokinesis. The interaction between NabKin and F-actin is negatively regulated by Importin-ß and is responsive to spatial information provided by RanGTP. Disconnecting NabKin from F-actin during meiosis caused cytokinesis failure and egg polyploidy. We also found actin-bundling activity in Nabkin's somatic paralogue KIF14, which was previously shown to be essential for somatic cell division. Our data are consistent with the notion that NabKin/KIF14 directly link microtubules with F-actin and that such link is essential for cytokinesis.

Identification and characterization of a Golgi retention signal in feline coronavirus accessory protein 7b.

Feline coronaviruses encode five accessory proteins with largely elusive functions. Here, one of these proteins, called 7b (206 residues), was investigated using a reverse genetic approach established for feline infectious peritonitis virus (FIPV) strain 79-1146. Recombinant FIPVs (rFPIVs) expressing mutant and/or FLAG-tagged forms of 7b were generated and used to investigate the expression, processing, glycosylation, localization and trafficking of the 7b protein in rFIPV-infected cells, focusing on a previously predicted ER retention signal, KTEL, at the C-terminus of 7b. The study revealed that 7b is N-terminally processed by a cellular signalase. The cleavage site, 17-Ala|Thr-18, was unambiguously identified by N-terminal sequence analysis of a 7b processing product purified from rFIPV-infected cells. Based on this information, rFIPVs expressing FLAG-tagged 7b proteins were generated and the effects of substitutions in the C-terminal 202KTEL206 sequence were investigated. The data show that (i) 7b localizes to and is retained in the medial- and/or trans-Golgi compartment, (ii) the C-terminal KTEL sequence acts as a Golgi [rather than an endoplasmic reticulum (ER)] retention signal, (iii) minor changes in the KTEL motif (such as KTE, KTEV, or the addition of a C-terminal tag) abolish Golgi retention, resulting in relocalization and secretion of 7b, and (iv) a KTEL-to-KDEL replacement causes retention of 7b in the ER of rFIPV-infected feline cells. Taken together, this study provides interesting new insights into an efficient Golgi retention signal that controls the cellular localization and trafficking of the FIPV 7b protein in virus-infected feline cells.

Conformational Changes and Competitive Adsorption between Serum Albumin and Hemoglobin on Bioceramic Substrates.

Traditional methods to analyze interactions and conformational changes of proteins adsorbed onto biomaterials are limited by the protein's associations with the substrate material and the complexity of the surrounding media. We have used EPR spectroscopy in combination with site-directed spin labeling (SDSL) to investigate single protein and competitive adsorption kinetics of horse hemoglobin (Hgb) and bovine serum albumin (BSA) on a silica-calcium-phosphate bioceramic substrate. Combined continuous wave and pulsed (DEER) EPR techniques were employed to monitor local mobility/flexibility changes within the proteins and tertiary structure dynamics upon adsorption. An alternate labeling technique was introduced to allow for specific quantification of each protein adsorbed to the bioceramic surface. We show that at buffer pH 7.4 and 4.7 the amount of adsorbed hemoglobin was increased by a factor of 4-5 compared with BSA. The tertiary structure of hemoglobin was strongly affected upon adsorption, leading to a dissociation of the tetrameric molecule into monomers or αß dimers. When the bioceramic substrate was previously functionalized with a layer of BSA, dissociation was reduced by 71 % compared with the untreated surface, indicating a "primer" effect of BSA for better adhesion of the globular hemoglobin.

[Metabolic surgery or conservative measures as therapy of obese type 2 diabetics?] / Metabolische Chirurgie oder konservative Maßnahmen zur Behandlung adipöser Typ 2-Diabetiker?

After bariatric surgery there are some favourable effects on comorbidities of obesity as glucose and lipid metabolism besides weight loss. Therefore surgical measures targeting at improvement of such metabolic disorders especially diabetes type 2 has been called "metabolic surgery". The complexity of its underlying metabolic mechanisms is not yet clear, but restriction of energy and weight loss (maintenance) seem to be the cornerstones.Risks of these procedures which are drawn of the established methods of bariatric surgery are reported to be relatively low in qualified centers. Being an elective operation special focus has to be set on mortality and morbidity, numbers of therapeutic failure and redo-surgery. Multiple irreversible and not seldom severe, potentially life-threatening consequences of bariatric surgery require consequent interdisciplinary postsurgery care and therapy throughout the whole life, especially substitution therapy of deficiencies due to post-operative malassimilation, if necessary. Little is known about long term consequences of modified anatomy and function of digestive system caused by surgery, and there may be a delay of (many) years until manifestation of clinical problems.Obese diabetics (BMI ≥ 35 kg/m2) should primarily be treated conservatively in an "individualized" way. Metabolic surgery should not be considered earlier than failure of the conservative approach has to be stated (in this case as an "ultima ratio" in well defined trials). A broader use of metabolic surgery beyond this narrow frame is not yet supported by long-term evidence-based data showing its value and safety.

ATP-dependent Conformational Changes Trigger Substrate Capture and Release by an ECF-type Biotin Transporter.

Energy-coupling factor (ECF) transporters for vitamins and metal ions in prokaryotes consist of two ATP-binding cassette-type ATPases, a substrate-specific transmembrane protein (S component) and a transmembrane protein (T component) that physically interacts with the ATPases and the S component. The mechanism of ECF transporters was analyzed upon reconstitution of a bacterial biotin transporter into phospholipid bilayer nanodiscs. ATPase activity was not stimulated by biotin and was only moderately reduced by vanadate. A non-hydrolyzable ATP analog was a competitive inhibitor. As evidenced by cross-linking of monocysteine variants and by site-specific spin labeling of the Q-helix followed by EPR-based interspin distance analyses, closure and reopening of the ATPase dimer (BioM2) was a consequence of ATP binding and hydrolysis, respectively. A previously suggested role of a stretch of small hydrophobic amino acid residues within the first transmembrane segment of the S units for S unit/T unit interactions was structurally and functionally confirmed for the biotin transporter. Cross-linking of this segment in BioY (S) using homobifunctional thiol-reactive reagents to a coupling helix of BioN (T) indicated a reorientation rather than a disruption of the BioY/BioN interface during catalysis. Fluorescence emission of BioY labeled with an environmentally sensitive fluorophore was compatible with an ATP-induced reorientation and consistent with a hypothesized toppling mechanism. As demonstrated by [(3)H]biotin capture assays, ATP binding stimulated substrate capture by the transporter, and subsequent ATP hydrolysis led to substrate release. Our study represents the first experimental insight into the individual steps during the catalytic cycle of an ECF transporter in a lipid environment.

Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy--a randomized trial.

BACKGROUND: To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases. METHODS: In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT. RESULTS: Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938-0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950-0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001-1.049, p = 0.044) were related with an avoidance of SRE. CONCLUSIONS: In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. TRIAL REGISTRATION: Clinical trial identifier NCT 01409720. August 2, 2011.