Search

Studies of age-specific reproductive performance are fundamental to our understanding of population dynamics and the evolution of life-history strategies. In species with bi-parental care, reproductive ageing trajectories of either parent may be influenced by their partner's age, but this has rarely been investigated. We investigated within-individual age-specific performance (laying date and number of eggs laid) in wild female blue tits Cyanistes caeruleus and evaluated how the age and longevity of their male partner indirectly influenced the females' reproductive performance. Females showed clear age-dependence in both laying date and number of eggs laid. We found that female reproductive performance improved in early life, before showing a decline. Longer-lived females had an earlier laying date throughout their lives than shorter-lived females, but there was no difference in number of eggs laid between longer- and shorter-lived females. Within breeding pairs, the female's (age-specific) reproductive performance was not dependent on the age and longevity of the male partner. We conclude that the age and quality of the male partner may be of little importance for traits that are under direct female control. This article is protected by copyright. All rights reserved.

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure–lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure–lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.

Background: Systemic sclerosis is a rare autoimmune disease characterized by skin and organ fibrosis, and vasculopathy. Raynaud’s phenomenon is almost universally present in systemic sclerosis and can be the most debilitating symptom. Raynaud’s phenomenon may lead to the development of digital ulcers, potentially complicated by infection, tissue necrosis, and auto-amputation. Recommended treatments have variable efficacy. Methods: We report the case of a 30-year-old woman with diffuse systemic sclerosis suffering from severe Raynaud’s phenomenon and digital ulcers with digital tissue necrosis who was treated with combination therapy of an endothelin receptor antagonist and phosphodiesterase 5 inhibitor. In addition, we reviewed the literature on the topic. Results: Previous therapy with calcium-channel blockers, intravenous iloprost, and bosentan had all failed to control symptoms. We added sildenafil in combination with bosentan and observed a rapid and sustained treatment effect. Raynaud’s phenomenon severity, number of attacks, and attack duration decreased within 2 weeks of initiating treatment. Furthermore, this resulted in the healing of established digital ulcers. Conclusion: Our case report suggests that combination therapy may be a feasible treatment for the most severely affected and refractory patients. In our literature review, we found one retrospective study and three additional cases with similarly encouraging results.

Background Rheumatoid arthritis (RA) is characterized by symmetrical involvement of small and large joints. New treatment modalities have not only allowed to achieve clinical remission or low disease activity, but also to halt the radiographic progression of joint destruction. In some patients, the disease progresses and leads to joint destruction despite treatment with disease-modifying antirheumatic drugs (DMARDs). Occasionally, wrist arthritis leads to severe destruction of carpal bones with ankyloses, so-called “os carpale”. Severely destructive wrist arthritis in an asymmetrical, unilateral pattern has only rarely been reported in the literature and has not been systematically assessed (1). A severely destructive yet often symmetrical arthritis has been described in seronegative RA patients (2). Objectives To systematically analyze the presence of severely destructive unilateral wrist arthritis in a single-center, seropositive RA population and to identify risk factors for its development. Methods This is a single-center retrospective cohort study using routine clinical data. We performed a database search of our RA population for the presence of rheumatoid factor (RF) and/or anti-CCP antibodies (ACPA) from 2011 to 2017. Radiographs were assessed independently by two investigators for the presence of severely destructive unilateral wrist arthritis. Discrepancies were resolved by discussion. Epidemiological data including age, gender, disease duration, occupation, dexterity and smoking status were recorded. Patients with psoriasis, a family history of psoriasis or posttraumatic osteoarthritis were excluded. Past and current treatments were recorded. Conventional radiographs of the hands were scored using the modified Sharp score, magnetic resonance images were examined if available. Results We identified 1247 patients with either positive RF, ACPA, or both. After exclusion of non-RA diagnoses and radiograph review, 17 eligible patients were included in the study. Of these, 7 were excluded because of incomplete clinical data. All of the remaining ten patients were female (100%). Median age was 58.1 years (33-70), median disease duration was 15.5 years (1-22). Seven patients were right-handed, one was left-handed, in two patients, dexterity was not known. Six patients were smokers, two patients were non-smokers, in two patients, smoking status was not known. Median ACPA levels were 134,6 IU/ml (normal range Conclusion Severely destructive unilateral wrist arthritis represents a rare phenotype of RA. In our cohort, this type of joint involvement was only present in women, it occurred primarily in the dominant hand (75%), and in smokers (75%). The mean number of used DMARDs was very high. Further studies for assessing the prevalence of this entity, also in seronegative patients, are required. References [1] Cassone, et al. (2004), Clinical and Experimental Rheumatology [2] Nikiphorou, et al. (2016), BMC Musculoskeletal Disorders Disclosure of Interests Viktor Korendovych Consultant for: Novartis, Radovan Vasko Consultant for: Novartis, Speakers bureau: Lilly, Elena Nikiphorou: None declared, Jan-Gerd Rademacher: None declared, Gerhard A Muller Grant/research support from: Novartis Boehringer-Ingelheim, Consultant for: Lilly, PETER KORSTEN Grant/research support from: Novartis Boehringer-Ingelheim, Consultant for: Novartis Pfizer Lilly, Paid instructor for: Chugai, Speakers bureau: Novartis

peerReviewed

Spermatozoa represent the morphologically most diverse type of animal cells and show remarkable variation in size across and also within species. To understand the evolution of this diversity, it is important to reveal to what degree this variation is genetic or environmental in origin and whether this depends on species' life histories. Here we applied quantitative genetic methods to a pedigreed multigenerational data set of the collared flycatcher Ficedula albicollis, a passerine bird with high levels of extra-pair paternity, to partition genetic and environmental sources of phenotypic variation in sperm dimensions for the first time in a natural population. Narrow-sense heritability (h2 ) of total sperm length amounted to 0.44 ± 0.14 SE, whereas the corresponding figure for evolvability (estimated as coefficient of additive genetic variation, CVa ) was 0.02 ± 0.003 SE. We also found an increase in total sperm length within individual males between the arrival and nestling period. This seasonal variation may reflect constraints in the production of fully elongated spermatozoa shortly after arrival at the breeding grounds. There was no evidence of an effect of male age on sperm dimensions. In many previous studies on laboratory populations of several insect, mammal and avian species, heritabilities of sperm morphology were higher, whereas evolvabilities were similar. Explanations for the differences in heritability may include variation in the environment (laboratory vs. wild), intensity of sexual selection via sperm competition (high vs. low) and genetic architecture that involves unusual linkage disequilibrium coupled with overdominance in one of the studied species.

Background:Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and skin as well as organ fibrosis. The lungs, skin, and gastrointestinal care frequently affected. Primary biliary cholangitis (PBC) is an autoimmune disease of the liver associated with potential progression to liver fibrosis. More recently, these two disorders have been described as an overlapping entity, especially in patients with limited, anti-centromere (CENP-B) positive SSc (1). Here, we report the first results of a pilot study of shear wave elastography (SWE) in patients with SSc and SSc/PBC compared to PBC patients.Objectives:To assess liver stiffness in patients with SSc, SSC/PBC overlap, and PBC with shear wave elastography.Methods:We analyzed a sample of 10 SSc to 11 PBC patients. In all patients, a baseline US examination of the liver and liver stiffness measurement by 2D SWE were performed using a GE logiq E10 ultrasound machine. Normal values for SWE in healthy people have recently been published (2). Liver stiffness measurement was performed according to the recommendations of the manufacturer and the recommendations of the current “EFSUMB Guideline and Recommendation on the Clinical Use of Liver Elastography” (3). In addition, age, body mass index (BMI), and antibody profiles were assessed.Results:Of 8 SSc patients without PBC, 6 were anti-CENPB pos., 1 had Scl70, and 1 Pm/Scl antibody. Median age was 59.5 (47-71). Median BMI was 23.1 (19.6-25). 1 patient had SSc/PBC overlap, 1 had hepatic steatosis. 1 was positive for CENP-B/AMA-M2 antibodies, the other patient was Scl70 positive. Median age of these 2 patients was 55.5 (55-56), BMI was 23.86 (20.9-26.8). 11 patients with PBC were positive for AMA-M2 antibodies, median age was 58 (41-78) years, BMI was 27.8 (15.8-50.3). The differences were not statistically different. Liver stiffness is expressed in kPa. Measurements had an interquartile range/median ratio Figure 1.Conclusion:Our results indicate that SWE is a useful tool in for the non-invasive assessment of liver stiffness in SSc and SSc/PBC overlap. We will further increase the sample size, especially of patients with SSc/PBC overlap. Of note, other liver diseases, such as hepatic steatosis, have to be kept in mind when SWE is performed as they may contribute to liver stiffness.References:[1]Lepri G, Randone SB, Cerinic MM, Allanore Y. Systemic sclerosis and primary biliary cholangitis: An overlapping entity?: Journal of Scleroderma and Related Disorders [Internet]. 2018 Oct 25 [cited 2020 Jun 17]; Available from: https://journals.sagepub.com/doi/10.1177/2397198318802763[2]Petzold G, Hofer J, Ellenrieder V, Neesse A, Kunsch S. Liver Stiffness Measured by 2-Dimensional Shear Wave Elastography: Prospective Evaluation of Healthy Volunteers and Patients With Liver Cirrhosis. J Ultrasound Med. 2019 Jul;38(7):1769–77.[3]Dietrich CF, Bamber J, Berzigotti A, Bota S, Cantisani V, Castera L, et al. EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Long Version). Ultraschall Med. 2017 Aug;38(4):e48.Disclosure of Interests:Viktor Korendovych: None declared, Jan-Gerd Rademacher: None declared, Golo Petzold: None declared, PETER KORSTEN Speakers bureau: Abbvie, Pfizer, Boehringer-Ingelheim, Novartis, Chuigai, Sanofi, GSK, all unrelated., Consultant of: Abbvie, Pfizer, Boehringer-Ingelheim, Novartis, Chuigai, Sanofi, GSK, Gilead, Lilly, all unrelated., Grant/research support from: GSK, unrelated to this study.

Background:Lupus nephritis (LN) occurs in about 30-60% of patients with systemic lupus erythematosus (SLE). LN is associated with increased mortality. Currently, the diagnosis relies on histopathologic characteristics according to the ISN/RPS classification (1). This classification relies heavily on glomerular changes and may not accurately reflect all changes occurring in LN. For the description of transplanted kidney, the BANFF classification has been established which, in addition to glomerular changes, also incorporates tubular pathologies (2).Objectives:With the present study, we aim to describe histopathologic changes according to the BANFF classification in a single-center cohort of LN patients.Methods:We retrospectively recorded epidemiological, clinical and laboratory data of 58 patients with LN over a ten-year period. Histopathologic diagnoses according to ISN/RPS classification or the former WHO classification were also documented. We then re-analyzed representative kidney samples according to the BANFF classification and performed Spearman rank correlation for BANFF findings and creatinine at biopsy and 12 months as well as proteinuria at biopsy and at 12 months.Results:We analyzed 58 patients with LN. 9 were male, 49 were female. Median age was 38 (15-78) years. According to ISN/RPS, 3 had class I LN, 6 had class II, 14 had class III, 16 had class IV, 6 had class V, and 0 had class VI. Median eGFR at biopsy was 60 ml/min/1.73m2 (13-137). According to the BANFF classification, tubulointerstitial inflammation (ti) was associated with creatinine at 12 months. Proteinuria at 12 months was associated with interstitial fibrosis (ci) (Figure 1).Conclusion:In LN, the current ISN/RPS classification puts emphasis on glomerular changes. Nevertheless, for the long-term outcome, tubulointerstitial changes (tubulointerstitial inflammation and interstitial fibrosis) may at least be as important as glomerular changes. These findings have to be corroborated in larger cohorts with prespecified renal endpoints.References:[1]Weening et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. JASN 2004.[2]Jeong HY. Diagnosis of renal transplant rejection: Banff classification and beyond. Kidney Res Clin Pract 2020.Disclosure of Interests:Marlene Plüß: None declared, Samy Hakroush: None declared, Noah Niebusch: None declared, Björn Tampe: None declared, PETER KORSTEN Speakers bureau: Abbvie, Pfizer, Chugai, Sanofi, Boehringer-Ingelheim, GSK, Novartis, Consultant of: Abbvie, Pfizer, Chugai, Sanofi, Boehringer-Ingelheim, GSK, Novartis, Lilly, Gilead, Grant/research support from: GSK

Background:ANCA-associated vasculitis (AAV) can present with a wide range of symptoms, including acute kidney injury (AKI) requiring renal replacement therapy or diffuse alveolar hemorrhage (1). These two manifestations often require admission to an intensive care unit (ICU) and are associated with increased mortality. To predict ICU mortality, the Simplified Acute Physiology Score version 2 (SAPS2) is often used but has not been formally tested in AAV patients (2). In addition, it is cumbersome to assess.Objectives:To develop a novel, simplified formula to predict ICU mortality in an AAV ICU population from an academic tertiary care center.Methods:We retrospectively recorded clinical and laboratory parameters in patients admitted to our ICU from 2000-2018. We performed risk factor analysis using univariate and multivariate logistic regression. In the multivariate case we applied the least absolute shrinkage and selection operator (lasso) method for variable selection. We considered average marginal effects and partial dependence plots in order to describe the influence of various independent variables on the probability of death more specifically. We evaluated our new score by comparing the corresponding area under the curve (AUC) to the AUC corresponding to the established SAPS2 score.Results:We analyzed 58 patients with AAV (39 granulomatosis with polyangiitis, 19 with microscopic polyangiitis) with a mean age of 74±14 (GPA) and 73±12 (MPA). 19/39 (48.7%) of GPA and 9/19 (47.4%) were female. Reasons for admission included disease manifestations or infectious complications from treatment (e. g. pneumonia, urinary tract infection). In total, 13/58 (22.4%) patients died throughout the study (10 GPA, 3 MPA patients). Using a cut-off threshold of 40 for SAPS2, sensitivity and specificity for mortality were 0.92 and 0.60, respectively. Confidence interval for the AUC was [0.68,0.95]. In the fitted multivariate logistic regression model, lasso was applied for variable selection. The identified variables included: disease duration, pH, procalcitonin, hemoglobin, leukocytes on admission, coronary heart disease, and pneumonia on admission. The estimated mortality is given by the formula ƒ(β0 + β1χ1 + …+ β7χ7), where ƒ(u)=1/(1+exp(−u)). Table 1 shows the estimated mortality for various values of the new score.Table 1.Example scores predicting mortality using the novel formula.ScorePredicted mortality-2.20.1-1.10.2500.51.10.752.20.9Testing if the AUC corresponding to the new model is significantly larger than the one corresponding to the SAPS2 score as independent variable resulted in p-value of 0.037. To identify possible overfitting, a 5-fold cross validation was performed. This resulted in a CI for the AUC of [0.64,0.96], suggesting that the new score allows for simpler prediction of mortality.Conclusion:We developed a novel formula corresponding to a score which is able to simpler predict mortality in patients with AAV admitted to the ICU. We will test our formula in the available ICU database MIMIC III, which comprises a large dataset of ICU patients.References:[1]Kitching AR, Anders H-J, Basu N, Brouwer E, Gordon J, Jayne DR, et al. ANCA-associated vasculitis. Nature Reviews Disease Primers. 2020 Aug 27;6(1):1–27.[2]Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993 Dec 22;270(24):2957–63.Disclosure of Interests:PETER KORSTEN Speakers bureau: Chugai, Boehringer-Ingelheim, Sanofi Aventis, Abbvie, GSK, Novartis, Consultant of: Lilly, Gilead, Abbvie, Boehringer-Ingelheim, GSK, Novartis, Grant/research support from: GSK, Fabian Kück: None declared, Karaine Tejiozem Donfack: None declared, Radovan Vasko: None declared, Andreas Lena: None declared, Björn Tampe: None declared

Background:The anti-CD20 antibody rituximab (RTX) is approved for the treatment of rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV). In addition, RTX is used in a wide range of autoimmune diseases. Belimumab (BEL) is an anti-BAFF antibody approved for the treatment of non-renal systemic lupus erythematosus (SLE) in Europe. These agents are generally well-tolerated but severe adverse events (AEs) can occur. The frequency of and factors associated with AEs are currently unknown.Objectives:To identify adverse events with the use of B-cell directed therapies in a large population of RA, AAV, and SLE.Methods:This is a single-center retrospective cohort study using routine clinical data over a ten-year period (2010-2020). We recorded epidemiological and clinical data of patients receiving either BEL or RTX. Data included age, gender, type of disease, number and efficacy of infusions, patient-years and concomitant treatment. Patient records were screened for AEs, such as infections, anaphylaxis, occurrence of malignant disease, laboratory abnormalities and immunoglobulin (Ig) deficiency. Between group comparisons were performed.Results:Database screening yielded 445 patients treated with RTX and 23 with BEL. After exclusion of patients with incomplete data, 425 RTX and 23 BEL patients were analyzed.Our preliminary analysis of a sample of 60 of these 448 patients (184 patient-years) resulted in 43 patients (72%) with RA, 8 patients with AAV (13%), 5 patients with a renal disease, and 4 patients with mixed connective tissue disease, as well 23 SLE patients. 46 (77%) were female. In RA, a median of 13 treatments of 1000 mg were administered, corresponding to 3.37 patient-years per patient. Primary non-response occurred in 2 patients, secondary non-response in 13 patients. For AAV, a median of 8.4 treatments were given (3.3 patient-years), no treatment failure was detected. SLE patients received a median of 15 treatments.15 patients had infectious complications during treatment, 11 needed treatment. Herpes zoster infection occurred in 3 patients with RA. Three of the 8 patients with AAV had an infection requiring treatment. In SLE patients, only 2 developed infectious complications, and no Ig-deficiency occurred.Lymphopenia was the most common laboratory abnormality detected in 25 patients with RTX, 19 of whom had RA. Ig deficiency was common in RA, affecting 30% of patients. Deficiency of IgM and IgG was recognized in 5 patients each; 1 patient had low levels IgA.Neither the maintenance prednisolone dosage nor Ig deficiency were associated with risk for infection. However, lymphopenia appeared to be associated with risk for infection.Conclusion:Our preliminary data observe a 184 patient-year period. RTX and BEL were generally associated with few AEs. RA patients frequently had laboratory abnormalities (lymphopenia, Ig-deficiency) which did not necessarily translate to clinical events. Infections were more common in AAV, BEL was the best tolerated B-cell directed agent. Overall, our data are reassuring, but we suggest a more careful vigilance in AAV patients.Disclosure of Interests:Jan-Gerd Rademacher: None declared, Viktor Korendovych: None declared, PETER KORSTEN Speakers bureau: Abbvie, Sanofi Aventis, GSK, Chugai, Boehringer-Ingelheim, Novartis, Consultant of: Lilly, Gilead, Boehringer-Ingelheim, Novartis, GSK, Grant/research support from: GSK

Background:Systemic lupus erythematosus (SLE) can affect almost any organ system. Nevertheless, Lupus nephritis and neuropsychiatric manifestations (NPSLE) are associated with increased mortality (1). Therapeutic options include glucocorticoids, often pulse methylprednisolone (MP), and other immunosuppressive therapies. In refractory cases, therapeutic plasma exchange, rituximab, or intravenous immunoglobulins are often used (2). However, an optimal therapeutic strategy has not been established because NPSLE is an exclusion criterion in most clinical trials. In addition, NPSLE can present with a broad spectrum of manifestations ranging from cognitive dysfunction to severe and life-threatening disease with choreoathetosis or transverse myelitis (TM). In primary Sjögren’s syndrome (pSS), neurological manifestations most often include peripheral neuropathies, but TM has also been reported.Objectives:To analyze the clinical presentation and outcomes after treatment in severe, life-threatening NPSLE.Methods:We retrospectively analyzed clinical, laboratory, and imaging features in severe NPSLE manifestations in SLE and pSS patients at two tertiary academic centers (University Medical Center Göttingen, Germany, and ASST Spedali Civili Brescia, Italy) with a high volume of SLE patients. Severe NPSLE was defined as either severe movement disorder or extensive tetra- or paraplegia secondary to (longitudinally extensive) transverse myelitis.Results:Our retrospective chart review resulted in seven patients fulfilling the inclusion criteria (six with SLE and 1 with pSS). Of these, five were females (71.4%). Median age was 26 (16-55) years. Three were of Asian origin, four were of European descent. Median disease duration was 15 (2-228) months. Three patients presented with severe choreoathetosis, all had positive ANA, anti-dsDNA antibodies (abs), and complement consumption. Of note, all three had at least one positive antiphospholipid antibody (APLA). All patients received IV MP 1g x 3 and mycophenolate mofetil and achieved complete remission. Of the four patients with longitudinally extensive TM, all were ANA positive, only two had anti-dsDNA abs. None of them had APLA, and only one tested positive for anti-aquaporine-4 abs. Of all patients, only one had positive ribosomal P-abs. Patients with TM received IV MP 1g x 5 and either RTX (4 cycles with 375 mg/m2 or IVIg 0.4 g/kg/d x 5). All four TM patients improved; two improved markedly, two only moderately with residual deficits as assessed by EDMUS-grading scale and functional independence measure.Conclusion:Severe NPSLE, defined as choreoathetosis or TM require intensive treatment. While the former patients achieved complete remission, two of four patients with TM only achieved partial remission. Our data support the use of early and aggressive immunosuppressive therapy. Nevertheless, therapy for TM in the context remains insufficient and should be assessed in a controlled clinical trial setting.References:[1]Monahan RC, et al. Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands. Lupus. 2020 Dec;29(14):1892–901.[2]Papachristos DA, et al. Management of inflammatory neurologic and psychiatric manifestations of systemic lupus erythematosus: A systematic review. Semin Arthritis Rheum. 2020 Dec 17;51(1):49–71.Disclosure of Interests:PETER KORSTEN Consultant of: PK has received honoraria by Abbvie, Bristol-Myers-Squibb, Chugai, Gilead, Glaxo Smith Kline, Janssen-Cilag, Pfizer, and Sanofi-Aventis, all unrelated to this study., Grant/research support from: PK has received research grants from GSK, unrelated to this study., Marlene Plüß: None declared, Stefanie Glaubitz: None declared, Ala Jambus: None declared, Radovan Vasko: None declared, Bettina Meike Göricke: None declared, Silvia Piantoni: None declared

We read with great interest the recent article by Fiedman and Winthrop reporting a patient with granulomatosis with polyangiitis (GPA) being treated with rituximab (RTX), recurrent SARS-CoV-2 disease 2019 (COVID-19) and no detectable SARS-CoV-2 seroresponse after recovery.1 Anti-CD20 therapy impairs humoral response, theoretically increasing the risk of prolonged SARS-CoV-2 infection and shedding as well as subsequent reinfection.1–3 We have recently reported a patient with GPA under maintenance therapy with RTX and SARS-CoV-2 infection.4 Here, we report further details on anti-CD20 therapy with RTX, serological response to SARS-CoV-2 infection, virus elimination and corresponding B cell numbers. This case highlights that B cell numbers in patients with rheumatic diseases treated with RTX could associate with serological response to SARS-CoV-2 infection, which is particularly relevant as RTX may also impair the immunogenicity of SARS-CoV-2 vaccines. An 80-year-old man had received a diagnosis of GPA in 2014 with biopsy-confirmed renal vasculitis and no history of pulmonary manifestation. After remission induction therapy, he received RTX at a dose of 500 mg every 6 months as maintenance therapy. The last …

Background: Sarcoidosis is a chronic multisystem disease of unknown etiology characterized by noncaseating granulomas that most often involves the lungs, but frequently has extrapulmonary manifestations, which might be difficult to treat in individual patients. Objective: To review different disease manifestations, focusing on extrapulmonary organ systems, and to provide treatment options for refractory cases. Materials and methods: We performed a literature search using Medline and Google Scholar for individual or combined keywords of “sarcoidosis, extrapulmonary, treatment, kidney, neurosarcoidosis, cardiovascular, gastrointestinal, transplantation, musculoskeletal, rheumatology, arthritis, and skin”. Peer-reviewed articles, including review articles, clinical trials, observational trials, and case reports that were published in English were included. References from retrieved articles were also manually searched for relevant articles. Results and conclusion: Isolated involvement of a single organ or organ system is rare in sarcoidosis, and thus all patients must be thoroughly evaluated for additional disease manifestations. Cardiac sarcoidosis and neurosarcoidosis may be life-threatening. Clinicians need to assess patients comprehensively using clinical, laboratory, imaging, and histopathological data to recommend competently the best and least toxic treatment option for the individual patient. peerReviewed

Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (methotrexate, azathioprine, leflunomide) and third-line agents (infliximab, adalimumab). Other immunmodulating agents can be used, but the evidence is very limited. Newer agents with anti-fibrotic properties, such as pirfenidone or nintedanib, might hold promise also for the pulmonary fibrosis seen in sarcoidosis. Treating physicians have to actively look for potentially treatable complications, such as pulmonary hypertension, cardiac disease or infections before patients should be classified as treatment-refractory. Ultimately, lung transplantation has to be considered as treatment option for patients not responding to medical therapy. In this review, we aim to propose a new definition of refractoriness, describe the associated clinical features and suggest the therapeutic approach.

Most birds have specific habitat requirements for breeding. The vegetation structure surrounding nest sites is an important component of habitat quality, and can have large effects on avian breeding performance. We studied 13 years of Blue Tit Cyanistes caeruleus population data to determine whether characteristics of vegetation structure predict site occupancy, laying date and number of eggs laid. Measurements of vegetation structure included the density of English Oak Quercus robur, European Beech Fagus sylvatica, and other deciduous, coniferous and non-coniferous evergreen trees, within a 20-m radius of nest-boxes used for breeding. Trees were further sub-divided into specific classes of trunk circumferences to determine the densities for different maturity levels. Based on Principal Component Analysis (PCA), we reduced the total number of 17 measured vegetation variables to 7 main categories, which we used for further analyses. We found that the occupancy rate of sites and the number of eggs laid correlated positively with the proportion of deciduous trees and negatively with the density of coniferous trees. Laying of the first egg was advanced with a greater proportion of deciduous trees. Among deciduous trees, the English Oak appeared to be most important, as a higher density of more mature English Oak trees was associated with more frequent nest-box occupancy, a larger number of eggs laid, and an earlier laying start. Furthermore, laying started earlier and more eggs were laid in nest boxes with higher occupancy rates. Together, these findings highlight the role of deciduous trees, particularly more mature English Oak, as important predictors of high-quality preferred habitat. These results aid in defining habitat quality and will facilitate future studies on the importance of environmental quality for breeding performance. (C) 2015 Elsevier Masson SAS. All rights reserved.

In the pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19), patients with immunosuppressive therapies have a potentially more severe course of the disease. While recent data from the registry of the Global Rheumatology Alliance have been reassuring regarding the use of biological disease-modifying antirheumatic drugs (bDMARDs), no definite recommendations can be made regarding specific bDMARDs.1 In their recent letter, Nuno and coworkers describe a large cohort of 122 patients with rheumatic diseases.2 Most interestingly, higher hospitalisation rates and more severe and life-threatening cases of COVID-19 have been described with the use of rituximab (RTX).2–4 To the best of our knowledge, we here describe the first reported case with repeated false-negative tests and a delayed diagnosis of COVID-19 in a patient with granulomatosis with polyangiitis (GPA) under maintenance therapy with RTX and concomitant influenza pneumonia. An 80-year-old man presented to the emergency department with a 2-week history of productive cough. The patient had received a diagnosis of GPA in 2014 with biopsy-confirmed renal vasculitis and no history of pulmonary manifestation. After remission induction, he received RTX at a dose of 500 mg every 6 months as maintenance therapy. A staging CT of the chest 2 weeks prior to …

Purpose Antiphospholipid syndrome (APS) is a severe and potentially life-threatening condition. Most commonly, it presents with arterial or venous thrombotic complications. Unusual presentations might lead to a delay in diagnostic and therapeutic measures. Purpura fulminans (PF) is a rarely reported manifestation. Methods Case report at a single centre. Results We present the case of a 25-year-old female who developed purpura fulminans after evacuation of a perimandibular abscess. The patient was initially admitted to an external maxillofacial surgery unit for incision and drainage of a perimandibular abscess after multiple episodes of tonsillitis. Her past medical history includes a significant spontaneous deep venous thrombosis 8 months prior to admission. APS had been suspected in view of one pathological lupus anticoagulant result, but a diagnosis had not been made at the time. The patient was anticoagulated with Rivaroxaban and had experienced no further events. Lupus serology remained negative. Immediately after maxillofacial surgery, the patient developed lightning bolt-shaped hematomas with peripheral blisters and central necrosis on both arms, her right thigh, the back of her neck and torso, as well as both earlobes. She was diagnosed with PF and transferred to our rheumatology unit, where her medical management was adjusted with a switch from oral anticoagulation to low-molecular weight heparin and initiation of oral corticosteroid therapy. Further testing confirmed the working diagnosis of APS: a pathological lupus anticoagulant, raised anti-cardiolipin IgM and IgG, positive beta-2 glycoprotein, high aPTT, and low complement C3. A skin biopsy demonstrated multiple thrombi in blood vessels of the dermis. In light of this result and further clinical deterioration of the PF even under oral steroid therapy, treatment was escalated to five sessions of plasma exchange. With this treatment, the patient’s condition improved drastically. There were no further purpura or blisters and the existing skin lesions lightened and grew smaller. Anticoagulation was switched from heparin to Warfarin and the patient was discharged on a tapering dose of oral Prednisolone. Conclusion PF is a rare presentation of APS. This case demonstrates the value of early and resolute escalation of treatment. Plasma exchange is a potentially life-saving treatment modality in this setting.

Purpose Belimumab (BEL) is approved for Systemic Lupus erythematosus in addition to standard immunosuppressive therapies. Clinical studies have excluded patients with particular organ manifestations from participation in most clinical trials. Most importantly, Lupus nephritis (LN) and neuropsychiatric Systemic Lupus erythematosus (NPSLE) were exclusion criteria in the relevant clinical studies. We aim to report our experience of BEL’s effect on SLE manifestations which have not been formally addressed in clinical trials. Methods We performed an observational study of routinely collected clinical data of all patients receiving BEL with or without other immunosuppressive therapy at our institution. Results We identified 15 patients currently receiving BEL therapy. Of these, 9 were not analysed further because they had no history of LN or NPSLE. One 48-y/o female patient after renal transplantation with background therapy consisting of prednisone (GC), hydroxychloroquine (HCQ), leflunomide (LEF) and tacrolimus (TAC) had a stable disease but no additional benefit (BEL stopped after 5 months). Three female patients with GC, HCQ and mycophenolate mofetil (MMF) had an improvement of proteinuria, steroid dosage and overall quality of life. One female patient is receiving BEL or placebo (PBO) during a clinical trial (BLISS-LN), she has markedly improved proteinuria with GC, HCQ, MMF and BEL/PBO. One 73-y/o male patient with NPSLE who failed or could not tolerate various standard and additional therapies (including Rituximab and Cyclophosphamide) had a persistent clinical improvement of cutaneous lupus and neuropsychiatric symptoms (dysarthria, concentration, ataxia) after the second BEL infusion. Overall, there was one upper respiratory tract infection but no other adverse events. Conclusions In the six patients analysed, 3 had improved proteinuria, 1 had stable disease after renal transplantation, 1 improved regarding NPSLE symptoms and 1 had improved proteinuria, but in the last case, it is not yet clear whether the effect is due to BEL. Overall, while the results of the BLISS-LN trial are awaited, we experienced improved Lupus nephritis with BEL in addition to standard therapy and observed one case of improved NPSLE. While BEL has not been approved for these severe organ manifestations, it still might be effective in well-selected patients.

Purpose In systemic lupus erythematosus (SLE), lupus nephritis (LN) represents one of the most severe organ complications. LN is associated with persistent inflammation and perpetuated fibroblast activation, both determined by epigenetic mechanisms involving aberrant CpG DNA promoter methylation. During SLE progression, global methylation patterns are commonly lost. CpG DNA promoter methylation patterns are not limited to the kidney, circulating CpG-rich DNA is also detectable in the blood. However, little is known about its specific contribution to determining disease progression. In the kidney, CpG-rich DNA activates TLR9 signalling mechanisms involved in inflammation and fibrogenesis. Based on these observations, we hypothesised that CpG-rich DNA promoter fragments potentially accelerate renal inflammation and fibrogenesis in SLE-associated LN. Methods First, CPG-rich DNA from blood samples of SLE patients with and without LN were collected. Then, we tested how these DNA promoter fragments influenced the LN phenotype in a TMPD (‘pristane’)-induced mouse model. The renal response to the administration of either human or synthetic methylated/unmethylated CpG-rich DNA oligodinucleotides (ODN) was observed. Downstream effects of the administration of circuclating CpG-rich DNA fragments on TLR9-signalling were analysed in endothelial cell cultures. Results Circulating CpG-rich DNA promoter fragments are detectable in SLE patients‘ blood. LN was associated with accumulation of unmethylated CpG-rich DNA promoter fragments, implicating a mechanistic link. In a rodent model of pristane-induced lupus, administration of CpG-rich DNA (isolated from LN patients or synthetic unmethylated CpG-rich DNA ODN) worsened the renal phenotype. TLR9-mediated intrarenal inflammation can be therapeutically targeted by administration of synthetic methylated CpG-rich DNA oligonucleotides, ultimately associated with suppression of TLR9-mediated signalling responses and renal injury in experimental LN. Conclusions Our results implicate accumulation of unmethylated CpG-rich promoter DNA fragments in LN. Furthermore. these unmethylated CpG-rich promoter DNA fragments causally contribute to TLR9-mediated inflammation and renal fibrogenesis and administration of methylated CpG-rich ODN attenuated intrarenal TLR9-mediated inflammatory signalling responses. Therefore, biomonitoring of CpG-rich promoter DNA fragments and modulation of intrarenal TLR9 signalling might be a promising therapeutical target in LN.

Summary Parental care, a central component of reproduction in a wide range of animal species, often involves elaborate behavioural interactions between parents and their offspring. Due to the reciprocal nature of these interactions, it has been hypothesized that parental and offspring behaviours (e.g. parental food provisioning and offspring begging) are not only target but also agent of selection. These traits are therefore expected to co-evolve, ultimately leading to co-adaptation of parent and offspring behaviours within families. However, empirical data on such parent–offspring co-adaptation are limited, particularly for wild populations. Furthermore, mean levels of behaviour (as measured in previous studies) may not adequately describe the dynamic nature of the reciprocal interplay between parents and their offspring, and instead rather the behavioural reaction norms for provisioning and begging may be co-adapted. We applied a large-scale cross-fostering study over 3 consecutive breeding seasons to investigate whether provisioning behaviour of wild blue tit (Cyanistes caeruleus) parents covaries with the begging behaviour of their genetic, cross-fostered offspring. We simultaneously analysed parent and offspring behaviours, both as static traits (mean levels) and behavioural reaction norms (offspring begging as a function of food deprivation and parental provisioning as a function of short-term experimental changes in brood size). Neither maternal nor paternal provisioning rates covaried with the begging intensity of their genetic offspring when analysed as mean levels of behaviour. However, the slopes of the reaction norms for provisioning and begging were negatively correlated between male, but not female, parents and their genetic offspring. Thus, fathers that change their provisioning rate strongly with brood size sire offspring whose level of begging only weakly increases with hunger, and vice versa. The observed covariation suggests the existence of sex-specific optima for parent–offspring trait combinations. Thus, our study not only highlights the importance of a behavioural reaction norm approach when investigating parent–offspring interactions, but also stresses the relevance of considering parents as separate units, at least for biparental species.

Background Chronic sarcoidosis is a systemic disease of unknown etiology, characterized by the histological finding of granulomas in involved organ systems. The most often affected organ is the lung with approximately 90–95%. Systematic data of organ manifestations other than the lung are scarce and show a wide range from 1–2% up to 50% depending on the series. Methods We analyzed data of newly diagnosed chronic sarcoidosis in 3 tertiary hospitals. We analyzed data on organ manifestations (OM), type of OM and laboratory findings. The certainty of OM was classified as grade 0 (not investigated), grade 1 (no sign of OM), grade 2 (clinical sign of OM), grade 3 (signs of OM in laboratory findings or imaging) and grade 4 (histological proven OM), respectively. Results We included 151 patients with biopsy-proven chronic sarcoidosis. Mean age was 50.8±15 years with a male predominance (87 [57.2%] vs. 65 [42.8%] patients). Except for 3 patients, all demonstrated pulmonary involvement. The predominant type of lung involvement was type I (mediastinal lymph node enlargement) in 54.2% and type II (mediastinal lymph node enlargement and interstitial involvement) in 27.7%. 96.5% of patients were investigated for an affection of the kidneys, 97.3% for hepatic, 92.7% for skin involvement, 68.8% for ocular manifestations, 67.5% for ear, nose, throat (ENT) manifestations and 92% for cardiac manifestations, respectively. Grade 3 (imaging/laboratory) and grade 4 (histology) findings were seen in the kidneys in 7.6/22.8%, in the liver in 13.3/11.9%, in the heart in 10.6/0.7%, in the eyes in 6.6/ Conclusions OM in chronic sarcoidosis are more frequent than suggested in the current literature, especially renal and hepatic. About 20% of patients with chronic sarcoidosis suffered from moderate to severe CKD due to sarcoidosis, which is a major organ complication contributing to overall morbidity. We recommend a systematic screening for OM in all patients with chronic sarcoidosis as it is performed in other systemic rheumatic disease. Disclosure of Interest None declared

Background Rheumatologists are often confronted with systematic and rare diseases. Even among the rare diseases, clinical features may overlap, but treatment options for different diseases may differ. Objectives To illustrate the diagnostic challenges the clinician is confronted with when facing rare and systemic diseases in clinical practice with a case report where clinical features were overlapping. Methods A 64-year-old woman was presented to our institution after suffering from two ischemic strokes. Cerebral imaging was suggestive of large-vessel vasculitis. Additionally, imaging also revealed a left-sided retro-orbital mass. Her past medical history was notable for retroperitoneal fibrosis with ureteral obstruction requiring percutaneous drainage six months before presentation and placement of a cardiac pacemaker several years ago. Treatment with high-dose prednisone had been initiated but showed no clinical or laboratory improvement. Results Clinical examination revealed mild persistent facial hemiparesis and difficulty with ambulation. Mild exophthalmos was present on her left side. On palpation, there were palpable axillary masses bilaterally. Otherwise, her physical examination was normal. Laboratory analysis revealed elevated soluble interleukin-2 receptor levels at 2800 IU/mL (N: 230–770 IU/mL) and mildly increased C-reactive protein at 10 mg/L (N: Conclusions Erdheim-Chester disease (ECD) and IgG4-related disease are very rare disorders and can present with similar clinical findings, such as retroperitoneal fibrosis, alveolitis or lymph node enlargement. About 500 cases of ECD worldwide have been reported. ECD is a non-Langerhans cell histiocytosis with a reported five-year survival rate of about 68%. Roughly 50% of patients show a BRAF mutation. Various treatment options have been reported and are recommended by the recently published consensus guidelines (1). These include interferon-alpha, vemurafenib and also TNF-alpha inhibitors, such as infliximab, but also interleukin-antagonists, such as anakinra (IL-1) or tocilizumab (IL-6). Rheumatologists have to consider non-Langerhans cell histiocytoses in the differential of systemic diseases because the distinction can be difficult and imaging, as well as meticulous histopathologic analyses, are necessary to correctly diagnose these patients because treatment differs. References Diamond EL et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood 2014 Jul 24;124(4):483–92. Disclosure of Interest None declared

Background In systemic lupus erythematosus (SLE), lupus nephritis (LN) is associated with chronic inflammation and perpetuated fibroblast activation, both determined by epigenetic mechanisms involving aberrant CpG DNA promoter methylation. During SLE progression, global methylation patterns are commonly lost. These CpG DNA promoter methylation patterns are not limited to the kidney, circulating CpG-rich DNA is also detectable in the blood allowing for biomonitoring (“liquid biopsy”). However, little is known about its specific contribution to determining disease progression. In the kidney, CpG-rich DNA activates TLR9 signaling mechanisms involved in inflammation and fibrogenesis. Based on these observations, we hypothesized that CpG-rich DNA promoter fragments potentially accelerate renal inflammation and fibrogenesis in SLE-associated LN. Objectives To analyze the role of circulating CpG-rich DNA on endothelial TLR9 signalling and the effect of experimental modification of oligodinucleotides on kidney inflammation in the Pristane-induced murine model of SLE. Methods We isolated circulating CpG-rich DNA from blood samples in a cohort of SLE patients. Then, we tested how these DNA promoter fragments influenced the LN phenotype in a TMPD (“pristane”)-induced mouse model. Further, we investigated how this renal response could be influenced by the administration of either human or synthetic methylated/unmethylated CpG-rich DNA oligodinucleotides. Additionally, the effects of the administration of cicruclating CpG-rich DNA fragments on TLR9-signalling was analyzed in endothelial cell cultures. Results We show that circulating CpG-rich DNA promoter fragments are detectable in SLE patients9 blood. Furthermore, SLE-associated LN is associated with accumulation of unmethylated CpG-rich DNA promoter fragments, implicating a mechanistic connection. These observations were further corroborated in a rodent model of TMPD-induced SLE where administration of CpG-rich DNA (isolated from LN patients or synthetic unmethylated CpG-rich DNA oligonucleotides) worsened the renal phenotype in terms of inflammation and fibrogenesis. Causal contribution of TLR9 was further confirmed in Tlr9+/--knockout mice with protection from renal inflammation and kidney fibrosis after administration of unmethylated CpG-rich DNA promoter oligonucleotides. TLR9-mediated intrarenal inflammation can be therapeutically targeted by administration of synthetic methylated CpG-rich DNA oligonucleotides, ultimately associated with suppression of TLR9-mediated signaling responses and renal injury in experimental SLE/LN. Conclusions Collectively, our results implicate accumulation of unmethylated CpG-rich promoter DNA fragments in SLE-associated LN. Furthermore. these unmethylated CpG-rich promoter DNA fragments causally contribute to TLR9-mediated inflammation and renal fibrogenesis. Administration of methylated CpG-rich oligonucleotides antagonized intrarenal TLR9-mediated inflammatory signaling responses and fibrogenesis. Therefore, biomonitoring of CpG-rich promoter DNA fragments and modulation of intrarenal TLR9 signaling is a promising therapeutical target in SLE-associated LN. Disclosure of Interest None declared

RATIONALE:Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies. OBJECTIVES:We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units. METHODS:We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result. MEASUREMENTS AND MAIN RESULTS:Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents. CONCLUSIONS:Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters. CLINICAL TRIAL REGISTRATION:The study was registered with www.clinicaltrials.gov (NCT02661607).

Objective. To investigate the role of whole blood viscosity in digital ulcer (DU) development in patients with diffuse and limited Systemic sclerosis.Methods. A convenience sample of patients with Systemic sclerosis (SSc) was selected from the adult Rheumatology clinic at the University of Chicago. The study group consisted of patients with SSc (with ulcers present, a history of ulcers, and no ulcers); the control group consisted of matched healthy Rheumatology clinic staff. WBV was measured using a scanning capillary viscometer at different shear rates (1–1000 1/s).Results. Whole blood viscosity as measured by a scanning capillary viscometer was increased in patients with SSc compared to healthy controls (p<0.0001). Additionally, patients with present DU had significantly higher whole blood viscosity when compared to patients with a history of DU and patients with no history of DU (p<0.0001). These findings were most pronounced at lower shear rates between 1 and 10 1/s.Conclusion. Whole blood viscosity might be a contributing factor in DU development in patients with SSc. Further studies with larger patient cohorts are required to fully evaluate how increased WBV contributes to the development of DU and whether the currently available treatment options improve the microcirculation by influencing WBV.

In many animal species, extra-pair copulations (EPCs) are common and can increase fitness in both sexes. In males, EPCs can increase total reproductive output, whereas in females benefits of EPCs can be indirect through improving the genetic quality of their offspring. Males and females of many vertebrates show an increase in levels of the hormone testosterone (T) during the mating period. In males, T plays an important role in regulating mating behaviour including increasing their EPC rate. While much is known about the role of T in male mating behaviour, the role of T in female reproduction remains unclear. To study the influence of T on extra-pair paternity rates in females in a field setting, we created three experimental groups of female blue tits (Cyanistes caeruleus): treated with either T, flutamide (Flu; an androgen receptor blocker) or empty implants before egg laying. Subsequently, we scored the number of extra-pair offspring (EPO) in their broods. We also assessed the attractiveness of females treated with either T or Flu to males in mate choice trials in the laboratory. The overall proportion of EPO was lower for the T-implanted group compared with the control group, whereas Flu had no effect. Given that males did not show a preference for Flu- vs. T-treated females in the mate choice trials, it appears less likely that the reduction in EPO in the T-implanted females was due to a reduction in their attractiveness. T levels may have negatively influenced EPO rate by affecting female within-pair and/or extra-pair mating behaviour. Future behavioural studies should investigate how elevated T levels reduce the number of EPO.

OBJECTIVES: In emergency departments (EDs), overcrowding, workload complexity, and cost containment represent current operational problems. In this retrospective observational study, we analyzed the effects of a professional quality management (QM) system on patient flow, diagnostic validity, and hospital costs. MATERIALS AND METHODS: In 2005/2006, the main ED at the University Medical Center Goettingen was reorganized. A professional QM system according to DIN EN ISO 9001:2008 was introduced in 2008. In a retrospective observational study, we compared the number of cases, the spectrum of clinical diagnoses, the validity of diagnoses, and hospital costs in the ED before (2005) and 2 years after the introduction of the QM system (2010). RESULTS: In the ED at the University Medical Center Goettingen, the number of cases increased by 22.7% between 2005 and 2010. After the introduction of the QM system, a significant reduction in patients' length of stay within the ED was achieved (P

Wir prasentieren den Fall eines 48-jahrigen, lange in Deutschland lebenden Vietnamesen mit Endophthalmitis, Leberabszess sowie pulmonalen und zerebralen septischen Embolien. In der mikrobiologischen Diagnostik wurde Klebsiella pneumoniae nachgewiesen, eine systemische Mykose konnte ausgeschlossen werden. Das „K. pneumoniae invasive syndrome“ ist eine hierzulande seltene Krankheitsentitat. Sie verdeutlicht die Notwendigkeit eines dezidierten diagnostischen Vorgehens unter Berucksichtigung von pradisponierenden Faktoren wie Herkunft und Begleiterkrankungen.

Telomere length (TL) predicts health and survival across taxa. Variation in TL between individuals is thought to be largely of genetic origin, but telomere inheritance is unusual, because zygotes already express a TL phenotype, the TL of the parental gametes. Offspring TL changes with paternal age in many species including humans, presumably through age-related TL changes in sperm, suggesting an epigenetic inheritance mechanism. However, present evidence is based on cross-sectional analyses, and age at reproduction is confounded with between-father variation in TL. Furthermore, the quantitative importance of epigenetic TL inheritance is unknown. Using longitudinal data of free-living jackdaws Corvus monedula, we show that erythrocyte TL of subsequent offspring decreases with parental age within individual fathers, but not mothers. By cross-fostering eggs, we confirmed the paternal age effect to be independent of paternal age dependent care. Epigenetic inheritance accounted for a minimum of 34% of the variance in offspring TL that was explained by paternal TL. This is a minimum estimate, because it ignores the epigenetic component in paternal TL variation and sperm TL heterogeneity within ejaculates. Our results indicate an important epigenetic component in the heritability of TL with potential consequences for offspring fitness prospects., Author summary Telomeres are DNA-protein structures at chromosome ends and a short telomere length predicts reduced survival in humans, birds and other organisms. Variation in telomere length between individuals is thought to be largely of genetic origin, but telomere inheritance may be unusual because not only genes regulating telomere length are inherited, but a fertilised cell already has a telomere length (from the parental gametes). Using long-term individual-based data of jackdaw families (a small corvid species), we found that as fathers aged, they produced chicks with shorter telomeres. This suggests that telomere length inheritance has an epigenetic component. To investigate to what extent telomere length in the fertilised cell affects telomere length after birth, we compared telomere length over years within fathers with the telomere length of their consecutive offspring. This epigenetic component explained a substantial part (≥ one third) of the telomere length inheritance; whereas there was no such effect of maternal telomere length. The sex difference fits the idea that lifelong sperm formation leads to change in telomere length of the sperm cells, whereas female gametes are all formed before birth and their telomere length does not change over time.

The assessment of genetic architecture and selection history in genes for behavioural traits is fundamental to our understanding of how these traits evolve. The dopamine receptor D4 (DRD4) gene is a prime candidate for explaining genetic variation in novelty seeking behaviour, a commonly assayed personality trait in animals. Previously, we showed that a single nucleotide polymorphism in exon 3 of this gene is associated with exploratory behaviour in at least one of four Western European great tit (Parus major) populations. These heterogeneous association results were explained by potential variable linkage disequilibrium (LD) patterns between this marker and the causal variant or by other genetic or environmental differences among the populations. Different adaptive histories are further hypothesized to have contributed to these population differences. Here, we genotyped 98 polymorphisms of the complete DRD4 gene including the flanking regions for 595 individuals of the four populations. We show that the LD structure, specifically around the original exon 3 SNP is conserved across the four populations and does not explain the heterogeneous association results. Study-wide significant associations with exploratory behaviour were detected in more than one haplotype block around exon 2, 3 and 4 in two of the four tested populations with different allele effect models. This indicates genetic heterogeneity in the association between multiple DRD4 polymorphisms and exploratory behaviour across populations. The association signals were in or close to regions with signatures of positive selection. We therefore hypothesize that variation in exploratory and other dopamine-related behaviour evolves locally by occasional adaptive shifts in the frequency of underlying genetic variants.

A 28-year-old man with acutely impaired vision, headache, and fever was referred to the emergency room because of suspected meningitis. His vital signs on admission were: blood pressure, 110/75 mmHg; heart rate, 125/min; temperature, 38.5°C. Physical examination revealed the skin changes shown in the images. Transesophageal echocardiography was performed without delay and revealed a threadlike vegetation on the aortic valve. The laboratory findings were: WBC, 14 900/µL; platelet count, 30 000/µL; CRP, 147 mg/L (normal

Background: To identify differentially regulated serum proteins, we compared proteome profiles of sera from patients with rheumatoid arthritis (RA) and healthy controls using proteomics. Methods: Sera were collected from 43 patients with RA and 48 healthy volunteers. The samples were cleared of the most abundant major proteins by immunoaffinity chromatography. Serum protein profiles between the two groups were compared by two-dimensional differential gel electrophoresis (2D-DIGE) and differentially regulated proteins were studied using mass spectrometry. Results: We identified 26 differentially expressed serum proteins between patients with RA and healthy controls. A quantitatively significant change of protein levels was defined as at least 1.5-fold upregulation or 0.6-fold downregulation respectively. Using these criteria, patients with RA exhibited significantly higher levels of leucine-rich alpha-2-glycoprotein (p