Cost-effectiveness of adalimumab for rheumatoid arthritis in Germany.

BACKGROUND: In Germany, the clinical use of TNF-α inhibitors in the therapy of rheumatoid arthritis (RA) grew from 2 % of treated patients in 2000 to 20 % in 2008. In 2012, adalimumab was the bestselling drug in the statutory health insurance system with net expenditure of € 581 mio. OBJECTIVES: We aim to analyze the cost-effectiveness of adalimumab for the treatment of RA in Germany. METHODS: We set up an individual patient sampling lifetime model to simulate 10,000 hypothetical patients. The patients' functional status improves according to American College of Rheumatology response criteria. In each 6­month cycle, treatment might be discontinued due to loss of efficacy or adverse events. RESULTS: In the base case, patients gain 7.07 quality-adjusted life years (QALYs) with conventional synthetic therapy and 9.92 QALYs if adalimumab combination therapy is added to the treatment algorithm. The incremental cost-utility ratio (ICUR) is € 24,492 based on German list prices. After deducting mandatory rebates and taxes, the ICUR is € 17,277, comparing favorably to analyses in other countries. Adalimumab combination therapy lowers indirect costs from € 162,698 to € 134,363. The ICUR based on total costs is € 14,550 (€ 7,335 after deducting taxes and rebates). Sensitivity analysis shows that adalimumab combination therapy becomes a dominant treatment option for younger baseline populations, i. e. adalimumab is both more effective and less expensive for baseline age 30 due to savings in indirect costs. CONCLUSIONS: Our complex probabilistic model shows that estimation of cost-effectiveness for RA relies on the incorporation of indirect costs and a sufficiently long simulation horizon to capture the complete range of possible outcomes and the associated long-term benefits of biological treatment.

Static Magnetic Proximity Effect in Pt/NiFe2O4 and Pt/Fe Bilayers Investigated by X-Ray Resonant Magnetic Reflectivity.

The spin polarization of Pt in Pt/NiFe2O4 and Pt/Fe bilayers is studied by interface-sensitive x-ray resonant magnetic reflectivity to investigate static magnetic proximity effects. The asymmetry ratio of the reflectivity is measured at the Pt L3 absorption edge using circular polarized x-rays for opposite directions of the magnetization at room temperature. The results of the 2% asymmetry ratio for Pt/Fe bilayers are independent of the Pt thickness between 1.8 and 20 nm. By comparison with ab initio calculations, the maximum magnetic moment per spin polarized Pt atom at the interface is determined to be (0.6±0.1) µB for Pt/Fe. For Pt/NiFe2O4 the asymmetry ratio drops below the sensitivity limit of 0.02 µB per Pt atom. Therefore, we conclude, that the longitudinal spin Seebeck effect recently observed in Pt/NiFe2O4 is not influenced by a proximity induced anomalous Nernst effect.

Significance of MR angiography in the diagnosis of aberrant renal arteries as the cause of ureteropelvic junction obstruction in children.

PURPOSE: To determine the importance of MRI with contrast-enhanced MRA for the detection or exclusion of aberrant or obstructing renal arteries in ureteropelvic junction obstruction in children. MATERIALS AND METHODS: Key word-based search in RIS database (ureteropelvic junction obstruction/ MRI) and retrospective comparison of arterial findings from preoperative contrast -enhanced MRA and intra-operative inspection. From 2007 to 2013, 19 children with ureteropelvic junction obstruction underwent contrast-enhanced MRA. Based on the results of the MRI scan and MAG3 scintigraphy, the children were referred to surgery (Anderson-Hynes-pyeloplasty). RESULTS: An aberrant renal artery was diagnosed with MRI in 14 of 19 children, and intra-operative inspection confirmed 13 of those 14. In the remaining 5 children, no aberrant vessel could be observed in MRI and this was confirmed intra-operatively in 3 of the 5 cases, while in the remaining 2, an aberrant vessel was found. Of the 14 children with aberrant vessels, 12 underwent surgery due to assumed ureteral obstruction, which was confirmed by surgery in 11 cases. In one case, an aberrant artery was found intra-operatively, but obstruction could not be confirmed. In one of the 14 children, the vessel was found in MRI, but its obstructing character was negated via MRA, which was confirmed intra-operatively. In the diagnosis of aberrant and obstructing renal arteries, contrast-enhanced MRA presents 85% sensitivity and 80% specificity, with a positive predictive value of 0.8. CONCLUSION: MRI with contrast-enhanced MRA is suitable to detect aberrant and obstructing renal arteries. An obstructive effect of the aberrant vessel is to be assumed if the vessel has a close relationship to the ureteropelvic junction and if it is linearly stretched. KEY POINTS: • MRI with contrast-enhanced MRA is a sure method for the detection of aberrant renal arteries in children with ureteropelvic junction obstruction. • The obstructive effect of the aberrant vessel can be derived from the close proximity of the vessel to the ureteropelvic junction and from the streched course of the vessel.

Practice of dilatation after surgical correction in anorectal malformations.

BACKGROUND: In order to prevent stricture of the neoanus after surgical correction, regular dilatation is recommended. There is a lack of knowledge about the performance of anal dilatation and the occurrence of pain. The aim of our investigation was to describe the practice of dilatation and to identify possible risk factors for painful procedures. METHODS: Congenital Uro-Rectal Malformations Network is a German interdisciplinary multicenter research network. With standard questionnaires, physicians interviewed 243 patients and/or their parents at home, additional 103 patients born since 2009 were assessed through their treating physicians. RESULTS: In total, 88 % of the patients received dilatations. Treatment lasted for 7 months in median (range 1-156 months), until the age of 13 months (range 1-171 months). In 69 % painful dilatation was reported; without a significant differences in age or gender. In 32 % bleeding was reported. In 30 % at least one dilatation was performed under general anesthesia. In 11 % some kind of analgesia was used. Type of fistula, dilatations lasting longer than 10 months and Hegar size above 15 were relevant factors for experience of pain. There were about 16 % postoperative strictures of the neoanus, without reported differences in dilatation procedures; but there was a relation to type of malformation. CONCLUSION: Considering the high number of painful treatments, predictors for painful dilatations should be further clarified through standardized documentation and prospective evaluation in order to improve follow-up.

Iapetus: unique surface properties and a global color dichotomy from Cassini imaging.

Since 2004, Saturn's moon Iapetus has been observed repeatedly with the Imaging Science Subsystem of the Cassini spacecraft. The images show numerous impact craters down to the resolution limit of approximately 10 meters per pixel. Small, bright craters within the dark hemisphere indicate a dark blanket thickness on the order of meters or less. Dark, equator-facing and bright, poleward-facing crater walls suggest temperature-driven water-ice sublimation as the process responsible for local albedo patterns. Imaging data also reveal a global color dichotomy, wherein both dark and bright materials on the leading side have a substantially redder color than the respective trailing-side materials. This global pattern indicates an exogenic origin for the redder leading-side parts and suggests that the global color dichotomy initiated the thermal formation of the global albedo dichotomy.

Tunable few-electron double quantum dots and Klein tunnelling in ultraclean carbon nanotubes.

Quantum dots defined in carbon nanotubes are a platform for both basic scientific studies and research into new device applications. In particular, they have unique properties that make them attractive for studying the coherent properties of single-electron spins. To perform such experiments it is necessary to confine a single electron in a quantum dot with highly tunable barriers, but disorder has prevented tunable nanotube-based quantum-dot devices from reaching the single-electron regime. Here, we use local gate voltages applied to an ultraclean suspended nanotube to confine a single electron in both a single quantum dot and, for the first time, in a tunable double quantum dot. This tunability is limited by a novel type of tunnelling that is analogous to the tunnelling in the Klein paradox of relativistic quantum mechanics.

Does high field MRI allow an earlier diagnosis of multiple sclerosis?

BACKGROUND: High field magnetic resonance imaging (MRI) provides higher lesion load measurements in patients presenting with clinically isolated syndromes (CIS) suggestive of demyelination and has impact upon the classification of these syndromes and potentially, the diagnosis of multiple sclerosis (MS). PURPOSE: To investigate whether high field MRI can provide an earlier diagnosis of definite MS within the International Panel (IP) and Swanton criteria. METHODS: Forty patients presenting with CIS suggestive of MS were included. All patients received multi-sequence MRI at 1.5 Tesla (T) and 3T as well as a neurological assessment at baseline. Follow-up visits including MRI at both field strengths and neurological examinations were scheduled 3-4 and 6-7 months after the first clinical event. Based on MRI and clinical findings, fulfilled IP criteria as well as Swanton criteria were analysed. RESULTS: At baseline, the higher detection rate of inflammatory lesions using high field MRI leads to higher classifications according to the Swanton criteria in 15 % of the patients. One additional patient was diagnosed with dissemination in space according to Swanton and IP criteria. During follow-up, an earlier diagnosis of definite MS could not be accomplished, neither according to the IP nor to the Swanton criteria. CONCLUSION: Although high field MRI shows a higher detection rate of inflammatory brain lesion in CIS and MS patients with an influence according to MRI criteria, this influence does not lead to an earlier diagnosis of lesion dissemination in time and therefore definite MS.

High field MR imaging and 1H-MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis: correlation between metabolic alterations and diagnostic MR imaging criteria.

PURPOSE: To prospectively investigate metabolic changes in the normal-appearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to correlate these changes to conventional MR imaging findings in terms of MR imaging criteria. MATERIALS AND METHODS: Multisequence MR imaging of the brain and (1)H-MR spectroscopy of the parietal NAWM were performed in 31 patients presenting with CIS and in 20 controls using a 3. 0 T MR system. MR imaging criteria and International Panel criteria were assessed based on imaging, clinical and paraclinical results. Metabolite ratios and absolute concentrations of N-acetyl-aspartate (tNAA), myoinositol (Ins), choline (Cho), and total creatine (tCr) were determined. The metabolite concentrations were correlated with the fulfilled MR imaging criteria. RESULTS: In comparison to the control group, the CIS group showed significantly decreased mean tNAA concentrations (-8. 1%, p = 0. 012). Significant changes could not be detected regarding Ins, tCr and Cho. No significant correlations between absolute metabolite concentrations and MR imaging criteria were observed. Patients with and without a lesion dissemination in space showed no significant differences of their metabolite concentrations. CONCLUSION: As assessed by (1)H-MRS a significant axonal damage already occurs during the first demyelinating episode in patients with CIS. Conventional MR imaging in terms of diagnostic imaging criteria does not significantly reflect NAWM disease activity in terms of metabolic alterations detected by (1)H-MR spectroscopy.

Prognostic value of high-field proton magnetic resonance spectroscopy in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis.

INTRODUCTION: The aim of this study was to determine the prognostic value of metabolic alterations in the normal-appearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) with special regard to the prediction of conversion to definite MS. METHODS: Using a 3T whole-body MR system, a multisequence conventional MRI protocol and single-voxel proton MR spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls. Absolute concentrations of N-acetyl-aspartate (tNAA), myo-inositol (Ins), choline (Cho) and creatine (tCr) as well as metabolite ratios were determined. Follow-up including neurological assessment and conventional MRI was performed 3-4 and 6-7 months after the initial event. RESULTS: Nine patients converted to definite MS during the follow-up period. Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (-13.4%, P = 0.002) whereas nonconverters (-6.5%, P = 0.052) did not. The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance. No significant differences could be observed for tCr and Cho in either patient group. CONCLUSION: Axonal damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS.

Sublingual immunotherapy in pollen-induced seasonal rhinitis and conjunctivitis: a randomized controlled trial.

BACKGROUND: Sublingual immunotherapy (SLIT) is a recognized and safe treatment for allergic rhinitis and conjunctivitis. The aim was to evaluate the efficacy and safety of tablets for grass and rye pollen- induced rhinitis and conjunctivitis. METHODS: A double-blind, randomized, placebo-controlled trial was carried out over 9 months. 105 patients received a standardized grass/rye mix extract or a placebo using sublingual drops during the build-up phase. Drops were replaced by sublingual tablets during the maintenance phase (300 IR/daily). RESULTS: In patients that received active treatment, a significantly lower total symptom score (rhinitis and conjunctivitis) compared to the placebo group was observed (p = 0.038). The investigators' assessment revealed a significant improvement in favor of the active treatment group (p = 0.018). Skin reactivity to grass and rye pollen was significantly reduced in the active treatment group (p < 0.05). No statistical difference was observed between the two groups for serum-specific IgG4 levels. Side effects were local and mild, and no severe systemic reactions were reported. CONCLUSION: This study indicates that tablet-based sublingual immunotherapy was safe and significantly improved grass/rye pollen-induced rhinoconjunctivitis symptoms. It was also associated with a significant inhibition of the immediate skin response.

Higher sensitivity in the detection of inflammatory brain lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis using high field MRI: an intraindividual comparison of 1.5 T with 3.0 T.

The purpose of this study was to determine the sensitivities in the detection of inflammatory lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis at 3.0 T and 1.5 T. MR imaging of 40 patients at both field strengths was performed in separate sessions including contiguous axial slices of T2 turbo spin-echo (T2 TSE), fluid-attenuated-inversion-recovery (FLAIR) and pre- and postcontrast T1 spin-echo (T1 SE). Inflammatory lesions > 3 mm in size were counted and categorized according to their anatomic location. Lesion conspicuity was assessed on a five-point scale. At 3.0 T, 13% more white matter lesions could be identified on the FLAIR sequence and on the T2 TSE sequence. Compared to 1.5 T 7.5% more contrast-enhancing lesions were detected at 3.0 T. The higher detection rate at 3.0 T was significant for the infratentorial (p = 0.02) and juxtacortical (p < 0.01) region on the FLAIR as well as for the infratentorial (p = 0.03), juxtacortical (p = 0.02) and periventricular (p = 0.03) region on the T2 TSE sequence. The lesion conspicuity was significantly better at 3.0 T for FLAIR and T2 TSE sequences (p<0.01; p=0.01). In conclusion, high-field MRI at 3.0 T provides a significantly higher detection rate of inflammatory brain lesions especially in the infratentorial, juxtacortical and periventricular anatomic region.

Magnetic field symmetry and phase rigidity of the nonlinear conductance in a ring.

We have performed nonlinear transport measurements as a function of a perpendicular magnetic field in a semiconductor Aharonov-Bohm ring connected to two leads. While the voltage-symmetric part of the conductance is symmetric in the magnetic field, the voltage-antisymmetric part of the conductance is not symmetric. These symmetry relations are compatible with the scattering theory for nonlinear mesoscopic transport. The observed asymmetry can be tuned continuously by changing the gate voltages near the arms of the ring, showing that the phase of the nonlinear conductance in a two-terminal interferometer is not rigid, in contrast with the case for the linear conductance.

Imaging of inflammatory lesions at 3.0 Tesla in patients with clinically isolated syndromes suggestive of multiple sclerosis: a comparison of fluid-attenuated inversion recovery with T2 turbo spin-echo.

The aims of this study were to determine and compare the sensitivity of T2 turbo spin-echo (T2 TSE) and fluid-attenuated inversion recovery (FLAIR) sequences at 3.0 T in the detection of inflammatory lesions in patients with clinically isolated syndromes suggestive of multiple sclerosis. Forty-nine patients were examined with a 3.0 T MRI system using 5 mm axial sections of T2 TSE (2:19 min), FLAIR (4:00 min) and pre- and postcontrast T1 spin-echo sequences (3:37 min). Brain lesions were counted and categorized according to their anatomic location. Patients were classified according to Barkhof MRI criteria for FLAIR and T2 TSE sequences. The FLAIR sequence detected more lesions in every anatomic region except for the infratentorial region. The higher sensitivity was significant for the total number of lesions (p<0.01), the juxtacortical (p<0.01), and the periventricular (p=0.01) region. A 9% increase of infratentorial lesions using the T2 TSE sequence was not significant. The higher sensitivity using the FLAIR sequence resulted in one additional MRI criterion in nine patients, whereas the better detection of infratentorial lesions using the T2 TSE sequence resulted in additional MRI criteria in three patients. In conclusion, FLAIR provides the highest sensitivity when compared with the T2 TSE, although T2 TSE still has a diagnostic relevance in terms of MRI criteria classification.

Langerhans'-cell histiocytosis in 58 adults.

Previous studies on Langerhans'-cell histiocytosis (LCH) were mostly retrospective and patients had been recruited over a long time period. The aim of the present study was to establish data on the clinical presentation, diagnosis and treatment of currently affected patients. Data on the clinical history, diagnostic work-up and course of histologically confirmed LCH in 58 adults were obtained with the aid of a questionnaire. A differentiation of the patients (average age 43.5 +/- 7.7 years, 66% women, 34% men) by the various clinical forms, revealed single-organ involvement in 42 of the patients (72 %), and multisystem involvement in the remaining 16 patients (28%). In the 42 patients, who had involvement of a single system, 23 had pulmonary involvement only. Multilocular osseous involvement was observed in 9 patients. In both single-organ or multisystem LCH the most common affected site was pulmonary involvement (62%), followed by osseous (50%) and cutaneous involvement (15%). 51 patients (88%) were smokers or ex-smokers. Dyspnoea (60%) and cough (47%) were the most frequent initial symptoms. In adults with LCH the pulmonary system is most frequently involved, however almost one-third of the patients present with multisystem disease.

[Multiple fibrofolliculomas]. / Multiple Fibrofollikulome.

Fibrofolliculoma is a rare tumor of the perifollicular mesenchyma. A 44-year old man noticed a growing number of small whitish firm papules on his neck and the upper thorax over the past two years. Histological examination demonstrated on multiple biopsies typical features of fibrofolliculoma. Further evaluation of the patient has not revealed any sign of neoplasia. The variable clinical manifestations of fibrofolliculomas are discussed.

[History of the teaching of odontotechnology at the University of Budapest]. / Az odontotechnika oktatásának története a budapesti egyetemen.

The teaching of odontotechnology at the University of Budapest has a more than 100 years history. It was started in the Academic Dental Institute led by József Arkövy. The first lecturer and practice instructor was Lajos Hattyasy. The first Institute of Odontotechnological Research was established in 1900, and was headed by the first "private docent" of the World appointed in Odontotechnology, Lajos Hattyasy. The Clinic of Stomatology in Budapest was opened in 1909 with European standard dental laboratory and practice rooms. The training program was extended to six semesters according to the act of the 1924 and 1936 Law of Education. In addition to odontotechnology the courses of dental materials and metals as well as restorative dentistry became independent preclinical subjects with a total of 670 teaching hours, making up 17% of the whole dental curriculum. That time Henrik Salamon and Dénes Máté were the chief lecturers. After World War II a new type of dental education started in 1952. The curriculum was extended to 10 semester with a great emphasis on odontotechnology. A very modern, phantom head preclinical training laboratory was opened in 1953. The total teaching time of odontotechnology was 360 hours and its theoretical principles were summarized in Hungarian second generation textbooks. That time Imre Földvári and György Huszár were the chief lecturers. From 1965 the significance of the course of odontotechnology was gradually diminishing and the teaching hours were markedly reduced. In 1967 odontotechnology as an independent subject was ceased and integrated into the prosthodontic dentistry. Its teaching time was reduced to 120 hours. In 1996 odontotechnology parallel with other preclinical subjects became independent again and earned a total of 260 teaching hours in the dental curriculum.

Coincidence of the molecular organization of beta-substituted oligothiophenes in two-dimensional layers and three-dimensional crystals

The molecular arrangements of three different alkyl-substituted oligothiophenes both in two-dimensional adsorbed layers at a substrate interface and in bulk three-dimensional crystals were studied. Scanning tunneling microscopy (STM) was used to investigate the ordering of the conjugated oligomers in two-dimensional layers adsorbed on graphite. These data were compared with the X-ray structure determinations of single crystals revealing the arrangement in the three-dimensional bulk material. Quaterthiophenes 1 and 2, bearing dodecyl and hexyl side chains, respectively, exhibit a lamella-type stacking of the conjugated backbone concomitant with an interlocking of the alkyl side chains both on the surface and in the crystal. In contrast, the arrangement of propyl-substituted quaterthiophene 3 is rather "herringbone-like" due to the reduced interactions of the shorter alkyl side chains. In all three cases, evidently, the two-dimensional ordering at the graphite surface is coincident with the molecular packing in one cross-section of the three-dimensional crystal.