[Development of quality standards for patients with axial spondyloarthritis for use in Germany]. / Entwicklung von Qualitätsstandards für Patient*innen mit axialer Spondyloarthritis zum Einsatz in Deutschland.

Quality standards (QS) are measurable constructs designed to quantify gaps in care and subsequently to improve quality of care. The Assessment of SpondyloArthritis International Society (ASAS) recently generated and published international QS for the management of patients with axial spondyloarthritis (axSpA) for the first time. The German Society of Rheumatology (DGRh) then decided to translate, review and possibly adopt these standards by a group of experts from different care settings. Against this background, national QS for the management of patients with axSpA for Germany were developed for the first time. The main focus was on feasibility and practical relevance. Ultimately, nine QS were defined with which the quality of care in Germany can and should be measured and improved.

[Standardized documentation of health-related quality of life in patients with psoriatic arthritis : Validation of the German version of the psoriatic arthritis quality of life (PsAQoL) questionnaire]. / Standardisierte Erfassung der gesundheitsbezogenen Lebensqualität bei Patienten mit Psoriasisarthritis : Validierung der deutschen Version des "Fragebogen zur Lebensqualität von Patienten mit Psoriasisarthritis (PsAQoL)".

BACKGROUND: The standardized assessment of health-related quality of life is becoming increasingly more important. The English questionnaire on psoriatic arthritis quality of life (PsAQoL) is a disease-specific instrument for measuring the quality of life of patients with psoriatic arthritis (PsA). The aim of the present study was to translate the PsAQoL into German and to validate the German version in a cohort of PsA patients recruited from routine care. METHOD: The translation and validation of the PsAQoL questionnaire was carried out in a stepwise procedure involving affected patients with PsA. After translation of the original English questionnaire the German version was evaluated in a field test. The psychometric features of the questionnaire were then examined in a PsA cohort from routine care. In addition to the construct and group validity, the reliability of the questionnaire was tested using test-retest reliability and internal consistency. The physical functioning was measured with the health assessment questionnaire (HAQ) and domains of the quality of life with the Nottingham health profile (NHP). RESULTS: In a field test with 10 patients the German version of the PsAQoL questionnaire proved to be relevant, easily understandable and feasible (processing time 4.7 ± 2.1 min). A total of 126 patients (37.3% male, age 55.6 ± 11.3 years) were included in the validation cohort. The PsAQoL showed moderate correlation with the HAQ (r = 0.65) and moderate to good correlation with the NHP (subdomains r = 0.58-0.75). The internal consistency was high (Cronbach's α 0.92) and reliability in patients with stable disease course was very good (Spearman correlation coefficient 0.94). The PsAQoL can differentiate between different patient groups. CONCLUSION: The German translation of the PsAQoL provides a valid disease-specific instrument for the standardized assessment of health-related quality of life in patients with PsA. The psychometric characteristics of this questionnaire are comparable with the original English version. The German PsAQoL can therefore be recommended for clinical and scientific application.

[Evaluation of a basic educational program for patients with rheumatoid arthritis]. / Evaluation einer Basisschulung für Patienten mit rheumatoider Arthritis.

BACKGROUND: A new conceptual framework has enabled the flexible development of rheumatological patient educational programs for different healthcare settings. On this basis, a 5­h basic training program for patients with rheumatoid arthritis (RA) was developed to be used in specialized centers. Rheumatologists and psychologists were first trained and then the efficacy of the patient training program was evaluated based on the causal model of patient education. METHODS: The externally randomized waiting control group study with 249 RA patients included 3 measurement points. The impact of the 5­h basic training on disease and treatment-related knowledge as well as health competence of RA patients was examined. Secondary questions included attitudinal parameters, communication competence, effects on the disease and satisfaction with the educational program. Data were analyzed on an intention to treat basis by means of covariance analyses for the main target variables, adjusted for baseline values. RESULTS: The analyses showed that the training program was effective. Even 3 months after training, participants reported more knowledge and health competence than the waiting control group, with small to medium-sized effects (d = 0.37 and 0.38, respectively). With the exception of disease communication, no other effects of training were observed in the secondary objectives. CONCLUSION: The basic training program provides a good foundation to develop further interventions to improve attitudinal and disease parameters. It can serve as a central component for rheumatological healthcare for patients with RA at various levels.

[Memorandum of the German Society for Rheumatology on the quality of treatment in rheumatology - Update 2016]. / Memorandum der Deutschen Gesellschaft für Rheumatologie zur Versorgungsqualität in der Rheumatologie ­ Update 2016.

On behalf of the Steering Committee of the German Society for Rheumatology, in 2016 the Interdisciplinary Commission on Healthcare Quality updated the 2008 memorandum on rheumatological healthcare in Germany. The update considers changes in therapeutic strategies, treatment targets as well as current structures in healthcare and the political framework. It concentrates on examination of the need for rheumatologists with a background in internal medicine and determines the gap between needs and supply. The internist rheumatologist is responsible for the care of patients with inflammatory rheumatic diseases and contributes to the care of patients with severe forms of other musculoskeletal diseases. At least 2 internist rheumatologists are needed for the outpatient care of 100,000 adult inhabitants, equivalent to 1350 rheumatologists in Germany. With currently 776 rheumatologists, we have little more than half of what we need. The German Society for Rheumatology calls for specific requirements planning for rheumatologists in outpatient care in order to decrease the deficit. In acute inpatient care we need specialized hospitals and wards that ensure a high quality of treatment for patients with complex diseases. We need up to 50 beds per 1 million inhabitants. At least 2 full-time internist rheumatologists and 3 further physicians are needed per 30 beds. In inpatient and outpatient rehabilitation we need 40 beds or outpatient places per 1 million inhabitants with at least 1 full-time rheumatologist and 1 further physician. In order to reduce the existing deficits and to cover the increasing future need for rheumatologists, more emphasis has to be laid on primary and secondary education. Chairs for internal rheumatology are needed at each medical university and more positions for postgraduate training in rheumatology should be provided. In all segments of healthcare the treatment aims should be jointly defined between patients and physicians. The patients should be treated in an interdisciplinary network, comprising other medical specialties, health professionals as well as patient organizations.

Does salmon calcitonin cause cancer? A review and meta-analysis.

Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship.

Stronger Limits on Hypothetical Yukawa Interactions in the 30-8000 nm Range.

We report the results of new differential force measurements between a test mass and rotating source masses of gold and silicon to search for forces beyond Newtonian gravity at short separations. The technique employed subtracts the otherwise dominant Casimir force at the outset and, when combined with a lock-in amplification technique, leads to a significant improvement (up to a factor of 10^{3}) over existing limits on the strength (relative to gravity) of a putative force in the 40-8000 nm interaction range.

Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo-controlled trial.

UNLABELLED: The effect of an investigational oral calcitonin tablet upon bone mineral density (BMD) of the spine was investigated in postmenopausal women with low bone mass and at increased risk of fracture. Compared to placebo, calcitonin tablets increased lumbar spine BMD. This agent may provide an additional choice for patients. INTRODUCTION: An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis. METHODS: Treatment-naïve women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording. RESULTS: One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups. CONCLUSIONS: Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass.

The positive influence of methotrexate on the mortality of patients with rheumatoid arthritis is partly independent of its effect on disease activity: results of a re-evaluation 18 years after baseline.

OBJECTIVES: Methotrexate (MTX) is the anchor drug in the treatment of patients with rheumatoid arthritis (RA). MTX shows effects on disease activity and mortality. However, it is unclear whether the effect of MTX on mortality depends on its effect on disease activity. METHODS: In a post-hoc analysis we analysed the data of our cohort established in Ratingen, Germany, and included all patients starting treatment with MTX (n=271) between 1980 and 1987. One year after baseline (BL), response to MTX treatment was assessed using a modified ACR 20 response. Follow-up data of 250 patients were available after 10 and 18 years. RESULTS: After 1 year, there were 66% responders and 20% non-responders; only 14% had discontinued MTX treatment due to side effects or lack of efficacy. Most patients continued MTX treatment irrespective of efficacy. Ten years after BL, 61% of the patients were still treated with MTX. After 18 years, the responder-group showed a standardised mortality ratio of 1.6 compared to 3.2 for the group of non-responders. However, when adjusting for age, gender, response to MTX treatment one year after BL, number of swollen joints and comorbidities after 10 years an independent association of continued MTX treatment with lower mortality was found for the period 10 to 18 years after BL (hazard ratio (HR): 0.63, 95% confidence interval: 0.43-0.92, p=0.015). CONCLUSIONS: In this cohort, the mortality lowering effect of continued MTX use was partly independent of its effect on disease activity. This finding may affect treatment decisions concerning RA patients with insufficient response to MTX.

Targeted 16S rRNA high-throughput sequencing to characterize microbial communities during composting of livestock mortalities.

AIM: A comprehensive understanding of the microbial community is necessary to ensure a significant reduction in pathogens during the composting process. METHODS AND RESULTS: Two biosecure, static composting systems containing cattle mortalities were constructed at subzero temperatures. Temperature at each sampling site was measured continuously and samples were grouped as either ≤50 or ≥55°C, based on temperature exposure required for effective pathogen inactivation during composting. High-throughput 454 sequencing was used to characterize the bacterial communities within each sample. Clustering of bacterial communities was observed according to temperature. However, neither richness nor diversity differed between temperature groups. Firmicutes was the most abundant phylum within both temperature groups but was more pronounced (63·6%) in samples ≥55°C (P < 0·05). Similarly, members of Clostridia, Clostridium sensu stricto (3·64%), Clostridium XI (0·59%), UF (Clostridiaceae 1) (5·29%) and UF (Clostridiales Incertae Sedis XI) (6·20%), were prominent at ≥55°C (P < 0·05), likely a reflection of spore survival and/or anaerobic microenvironments within passively aerated compost piles. Members of Thermobifida (3·54%), UO (Actinomycetales) (12·29%) and UO (Bacillales) (19·49%) were also prominent at ≥55°C (P < 0·05). CONCLUSION: Substantial spatial diversity exists within bacterial communities in field-scale compost piles. Localized temperature at the site of sampling may be one of the factors contributing to this phenomenon. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to describe the microbial community profile with the use of targeted 16S rRNA high-throughput sequencing in passively aerated composted livestock mortalities.

[Immunological treatment options for schizophrenia]. / Immunologische Behandlungsoptionen bei schizophrenen Störungen.

The pathophysiological mechanism leading to dopaminergic dysfunction in schizophrenia is still unclear. Inflammation seems to play a key role. A dysfunction in the activation of the type 1 immune response is associated with decreased activity of the key enzyme of the tryptophan/kynurenine metabolism, indolamine-2.3-dioxygenase (IDO), results in a higher production of kynurenine acid (KYNA)--an N-methyl-D-aspartate antagonist--in the central nervous system (CNS) and decreased glutamatergic neurotransmission. The differential activation of microglial cells and astrocytes, which serve as immune cells in the CNS, contributes to the TH1-TH2 immune imbalance. Antipsychotics, all acting as dopamine D2 receptor antagonists show several shortcomings. The immune effects of antipsychotics rebalance partly the imbalance of the type-1/type-2 immune response and the overproduction of KYNA. The inflammation is associated with higher prostaglandin E2 (PGE2) production and higher cyclo-oxygenase-2 (COX-2) expression. Increasing evidence from clinical studies with COX-2 inhibitors points to an advantageous effect of anti-inflammatory therapy in schizophrenia, especially in the early stages of the disease. Further options of immunomodulatory therapy in schizophrenia are discussed.

Vaccination of BALB/c mice with an avirulent Mycoplasma pneumoniae P30 mutant results in disease exacerbation upon challenge with a virulent strain.

Mycoplasma pneumoniae is a significant human respiratory pathogen that causes high morbidity worldwide. No vaccine to prevent M. pneumoniae infection currently exists, since the mechanisms of pathogenesis are poorly understood. To this end, we constructed a P30 cytadhesin mutant (P-130) with a drastically reduced capacity for binding to erythrocytes and an inability to glide on glass substrates. This mutant was determined to be avirulent and cannot survive in the lungs of BALB/c mice. We also ascertained that the previously identified P30 gliding motility mutant II-3R is avirulent and also cannot be recovered from the lungs of mice after infection. Mutant P130 was then assessed for its efficacy as a live attenuated vaccine candidate in mice after challenge with wild-type M. pneumoniae. After vaccination with the P-130 P30 mutant, mice showed evidence of exacerbated disease upon subsequent challenge with the wild-type strain PI1428, which appears to be driven by a Th17 response and corresponding eosinophilia. Our results are in accordance with other reports of vaccine-induced disease exacerbation in rodents and emphasize the need to better understand the basic mechanisms of M. pneumoniae pathogenesis.

The degree of spinal inflammation is similar in patients with axial spondyloarthritis who report high or low levels of disease activity: a cohort study.

BACKGROUND: The threshold for disease activity required to start antitumour necrosis factor (TNF) therapy has been arbitrarily set in patients with axial spondyloarthritis (axSpA) at Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4. How this relates to spinal inflammation is unknown. OBJECTIVE: To systematically compare the clinical, laboratory and imaging data of patients with axSpA with respect to their BASDAI level. METHODS: A total of 100 consecutive patients with axSpA who had never been treated with TNF blockers were included. Laboratory parameters, spinal MRI and x-rays were quantified. Data were stratified according to BASDAI ≥ 4. RESULTS: 44 patients were diagnosed as non-radiographic axSpA (nraxSpA) and 56 patients as ankylosing spondylitis (AS): median age 40.3 ± 10.4 years; 57% male, mean disease duration since diagnosis 6.4 ± 8.4 years, 88% HLA-B27+, mean modified Stokes Ankylosing Spondylitis Spinal Score 8.3 ± 16.4. 60% of patients had spinal inflammation by MRI. The stratification based on BASDAI ≥ 4 disclosed significant differences in most clinical parameters but not for inflammation: patients with nraxSpA and BASDAI < 4 versus ≥ 4 had 0.9 ± 1.4 and 0.5 ± 0.6 inflammatory lesions/patient, respectively (p=0.6), while patients with AS had 3.6 ± 3.7 and 2.7 ± 3.0 inflammatory lesions/patient, respectively (p=0.4). CONCLUSION: The burden of inflammation is quite comparable in patients with axSpA-regardless of disease activity. These data clearly challenge the concept of the recommended cut-off point of BASDAI ≥ 4.

Effects of subacute ruminal acidosis challenges on fermentation and endotoxins in the rumen and hindgut of dairy cows.

The effects of a grain-based subacute ruminal acidosis (SARA) challenge (GBSC) and an alfalfa-pellet SARA challenge (APSC) on fermentation and endotoxins in the rumen and in the cecum, as well as on endotoxins in peripheral blood, were determined. Six nonlactating Holstein cows with cannulas in the rumen and cecum were used in the study. A 3×3 Latin square arrangement of treatments with 4-wk experimental periods was adopted. During the first 3 wk of each experimental period, all cows received a diet containing 70% forages [dry matter (DM) basis]. In wk 4 of each period, cows received 1 of the following 3 diets: the 70% forage diet fed during wk 1 to 3 (control), a diet in which 34% of the dietary DM was replaced with grain pellets made of 50% ground wheat and 50% ground barely (GBSC), or a diet in which 37% of dietary DM was replaced with pellets of ground alfalfa (APSC). Rumen pH was monitored continuously using indwelling pH probes, and rumen fluid, blood, cecal digesta, and fecal grab samples were collected immediately before feed delivery at 0900 h and at 6 h after feed delivery on d 3 and 5 of wk 4. The time for which rumen pH was below 5.6 was 56.4, 225.2, and 298.8 min/d for the control, APSC, and GBSC treatments, respectively. Compared with the control, SARA challenges resulted in similar reductions in cecal digesta pH, which were 7.07, 6.86, and 6.79 for the control, APSC, and GBSC treatments, respectively. Compared with the control, only GBSC increased starch content in cecal digesta, which averaged 2.8, 2.6, and 7.4% of DM for the control, APSC, and GBSC, respectively. Free lipopolysaccharide endotoxin (LPS) concentration in rumen fluid increased from 10,405 endotoxin units (EU)/mL in the control treatment to 30,715 and 168,391 EU/mL in APSC and GBSC, respectively. Additionally, GBSC increased the LPS concentration from 16,508 to 118,522 EU/g in wet cecal digesta, and from 12,832 to 93,154 EU/g in wet feces. The APSC treatment did not affect LPS concentrations in cecal digesta and feces. All concentrations of LPS in blood plasma were below the detection limit of >0.05 EU/mL of the technique used. Despite the absence of LPS in blood, only GBSC increased the concentration of LPS-binding protein in blood plasma, which averaged, 8.9, 9.5, and 12.1mg/L for the control, APSC, and GBSC treatments, respectively. This suggests that GBSC caused translocation of LPS from the digestive tract but that LPS was detoxified before entering the peripheral blood circulation. The higher LPS concentration in cecal digesta in the GBSC compared with the APSC suggests a higher risk of LPS translocation in the large intestine in GBSC than in APSC.

Fatty liver disease is associated with underlying cardiovascular disease in HIV-infected persons(*).

BACKGROUND: Cardiovascular disease is an increasing concern among HIV-infected persons and their providers. We determined if fatty liver disease is a marker for underlying coronary atherosclerosis among HIV-infected persons. METHODS: We performed a cross-sectional study in HIV-infected adults to evaluate the prevalence of and factors, including fatty liver disease, associated with subclinical coronary atherosclerosis. All participants underwent computed tomography for determination of coronary artery calcium (CAC; positive defined as a score >0) and fatty liver disease (defined as a liver-to-spleen ratio <1.0). Factors associated with CAC were determined using multivariate logistic regression models. RESULTS: We included in the study 223 HIV-infected adults with a median age of 43 years [interquartile range (IQR) 36-50 years]; 96% were male and 49% were Caucasian. The median CD4 count was 586 cells/µL and 83% were receiving antiretroviral medications. Seventy-five (34%) had a positive CAC score and 29 (13%) subjects had fatty liver disease. Among those with CAC scores of 0, 1-100 and >100, the percentage with concurrent fatty liver disease was 8, 18 and 41%, respectively (P=0.001). In the multivariate model, CAC was associated with increasing age [odds ratio (OR) 4.3 per 10 years; P<0.01], hypertension (OR 2.6; P<0.01) and fatty liver disease (OR 3.8; P<0.01). CONCLUSIONS: Coronary atherosclerosis as detected using CAC is prevalent among young HIV-infected persons. The detection of fatty liver disease among HIV-infected adults should prompt consideration of assessment for underlying cardiovascular disease and risk factor reduction.

Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.

Sonic hedgehog, Patched and Gli are components of a mammalian signalling pathway that has been conserved during evolution and which has a central role in the control of pattern formation and cellular proliferation during development. Here we identify the human Suppressor-of-Fused (SUFUH) complementary DNA and show that the gene product interacts physically with the transcriptional effector GLI-1, can sequester GLI-1 in the cytoplasm, but can also interact with GLI-1 on DNA. Functionally, SUFUH inhibits transcriptional activation by GLI-1, as well as osteogenic differentiation in response to signalling from Sonic hedgehog. Localization of GLI-1 is influenced by the presence of a nuclear-export signal, and GLI-1 becomes constitutively nuclear when this signal is mutated or nuclear export is inhibited. These results show that SUFUH is a conserved negative regulator of GLI-1 signalling that may affect nuclear-cytoplasmic shuttling of GLI-1 or the activity of GLI-1 in the nucleus and thereby modulate cellular responses.