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Background Ambitious therapeutic goals in the therapy of inflammatory bowel disease need more stringent individual endpoints. Several definitions for composite endpoints are under evaluation to describe disease control. Most commonly symptomatic (PRO2) remission is combined with endoscopic response, histology and/or biomarker remission. Here we explore the addition of fatigues as a lead problem reported by patients with IBD as part of a composite endpoint. Methods We have conducted an interim analysis of an ongoing open label study of patients with Crohn’s disease (CD) and ulcerative colitis (UC) assigned to anti-TNF therapy, vedolizumab, ustekinumab or tofacitinib. Patients are scheduled for evaluations at start of the respective therapy and at weeks 2, 6, 14, 26 and 52. Endoscopies are conducted before therapy and at weeks 14 and 52. Clinical remission (CR) was defined as CDAI < 150 and reduction of partial Mayo score (pMayo) > 50% vs. baseline at week 14. All patients who are not in CR and/or no improvement in endoscopy at week 14 are assessed for a switch in the mechanism of action and observation schedules after a switch are reset to week 0. FACIT-F scores Results Fatigue was present in 52% patients (39/75) at baseline. 54% (25/46) of the patients achieved CR at week 14 while 46% (21/46) did not meet CR criteria (non-responder). Fatigue at baseline was persistent at week 14 in 12% (3/25) of CR responders, in contrast to 43 % (9/21) of non-responders. 64% (21/33) of all patients reached a combined endpoint of CR and absence of fatigue. If fatigue was present at baseline (n = 25), fatigue response was observed in 52% (13/25) of the patients, while CR was only reached in 40% (10/25) and the combined endpoint of CR and fatigue response in 24% (6/25) of the patients at week 14. In contrast, 71% (15/21) of patients without fatigue at baseline reached CR at week 14. Absence of fatigue at baseline thus increased the chance of CR at week 14, with an OR of 3.75 [1.031 – 11.50] (p = 0.0422 in Fisher’s exact test). Conclusion Fatigue is an important complaint strongly impacting the patients’ quality of life. A composite endpoint including fatigue and clinical remission (based on pMayo and CDAI) can be reached in a significant percentage of patients treated with biological therapies. Presence of fatigue at baseline might serve as a strong marker for clinical non-response at week 14. Further evaluation and replication of this novel composite endpoint will be conducted in our ongoing trial with a particular focus on inclusion of endoscopies and long-term outcome.

Background Currently available disease activity indices for IBD (e.g., CDAI and Mayo score) focus on symptoms directly related to intestinal function, while other relevant health consequences of disease activity including quality of life, neuropsychiatric symptoms like depression, and social functionality, are not captured. With better therapies more stringent definitions of patient health have come into focus. One of the most common patient reported outcomes (PROs) in IBD is fatigue, which can be unrelated to endoscopic disease activity. We have shown earlier a strong degradation of tryptophan in active IBD (Nikolaus et al, 2017, Gastroenterology) and low tryptophan levels have been linked in various chronic disease to high fatigue levels. Here, we aim to study the relationship of fatigue with disease activity in the context of therapy response to a biological treatment. Methods Patients with Crohn’s disease and ulcerative colitis with high disease activity (Mayo score ≥ 6, CDAI ≥ 220) and planned new therapy with a biologic agent were included into a prospective observational protocol. After informed consent, clinical disease activity, inflammatory biomarkers, tryptophan levels in serum and fatigue levels were assessed longitudinally at week 0, 2, 6 and 14 after start of induction therapy. Complete assessments including week 14 were available for 38 patients for this interim analysis of the ingoing study. For fatigue assessment we used the validated German version of the fatigue subscale of the FACIT-F questionnaire. Patients were stratified into therapy responder (clinical remission (CR), reduction of partal Mayo score (pMayo) > 50%, CDAI < 150), non-responders (reduction of Mayo Results In the cross-sectional analysis of all patients (n = 76), the fatigue score strongly (inversely) correlated with pMayo and CDAI and correlated positively with tryptophan levels in serum. In receiver operating characteristic (ROC) analysis, FACIT-F score were able distinguish active vs. non-active disease (p < 0.0001, AUC = 0.7619) with specificity of 0.7103 and sensitivity of 0.7160. We did not observe significant differences in fatigue scores between males and females. In the longitudinal analysis, fatigue score only improved in the CR group (n = 25, median FACIT score 30 at baseline vs. 44 at week 14, p = 0.0221), and was significantly higher in CR vs. non-responder (n = 16, median FACIT score 44 vs. 31.5, p = 0.007). Conclusion Fatigue is strongly related but not completely overlapping with disease activity. Fatigue will be evaluated as a a patient-oriented indicator for therapeutic response. This observation will be extended by increasing the cohort size and independent validation.

Background The role of nutrition in Inflammatory Bowel Disease (IBD) remains unclear. Studies about the effects of nutritional components on intestinal inflammation and the gut microbiome, as well as the concept of exclusive enteral nutrition in paediatric Crohn’s Disease (CD) are suggestive of an impact of nutrition on the pathophysiology. However, there is currently a lack of knowledge on how food components may affect IBD. Here, we investigated the T helper (Th) cell response against nutritional antigens in healthy controls and IBD patients. Methods We used a highly sensitive and specific method developed in our lab, the antigen reactive T cell enrichment (ARTE), to detect wheat and milk-reactive CD4+ T cells directly ex vivo in blood of healthy controls (n=18), CD (n=17) and Ulcerative Colitis (UC, n=15) patients. Peripheral blood mononuclear cells (PBMC) were incubated with whole antigen lysates and activated T helper cells were identified based on the up-regulation of the activation marker CD154. Magnetic enrichment of CD154 positive cells enabled to collect sufficient numbers of food-reactive T cells for their detailed characterization by multiparameter flow cytometry. Results We detected low frequencies of milk and wheat-reactive T cells in healthy individuals. Milk-reactive T cells were less frequent and expressed several markers of T cell exhaustion. In CD, but not UC patients, we identified higher frequencies of food-reactive T cells. These tended to be particularly increased in patients with disease manifestation in the upper gastrointestinal tract. In addition, we observed increased production of inflammatory cytokines of wheat-reactive T cells in CD, compared to healthy controls and UC patients. No ground-breaking differences were identified regarding the expression of exhaustion markers between IBD patients and controls. Conclusion Frequencies of food-reactive Th cells are increased in CD and show a proinflammatory cytokine pattern. The Th1-response of wheat-reactive T cells, characterized by high IFN-γ-secretion, might contribute to the perpetuation of chronic intestinal inflammation.

An industrial synthesis process for spherical lithium nickel cobalt mixed oxides, Li(Ni 1− y Co y )O 2 , has been successfully applied to aluminum- and magnesium-doped lithium nickel cobalt mixed oxides Li(Ni 1− y − z Co y M z )O 2 (M=Al, Mg). The additional elements stabilize the layered structure and enhance the cycling stability. The decomposition temperature of charged electrodes depends on the delithiation state and the crystallite size but not directly on the content of dopants. Therefore, enhancement of the thermal stability by aluminum and magnesium seems mainly to be an indirect effect due to an intrinsic limitation of the delithiation.

In comparison to pure electric vehicles (EV) the opportunities for hybrid electric vehicles (HEV) are much better, since range restrictions no longer apply and the interaction of the internal combustion engine and electrical drive bring increased energy efficiency and environmental friendliness. The batteries used in such applications must meet very high standards in terms of performance and service life. Although the battery capacity is smaller than for a purely EV, it needs to be able to generate far higher levels of power. The technical challenges of hybrid applications have led to the development of high-performance batteries. At the forefront of these is the nickel-metal hydride system (NiMH). With specific power and energy data in the range from 300 to 900 W/kg, 55 to 37 Wh/kg, respectively (based on cell weight), excellent charge efficiency and energy throughput levels of more than 10,000 times the nominal energy, the NiMH system comes very close to satisfying the needs of the HEV. Parallel developments with the lithium-ion system based on manganese spinel as cathode material show that, with specific power and energy levels above 1000 W/kg, 50 Wh/kg, respectively, this technology will also be able to play an important role in the future. Service life figures in terms of calendar life have been improved tremendously to about three years, but there is still a need for further improvement in order to meet the specifications of car manufacturers. For this reason, an increase of life span is the subject of intensive development work.

The dynamic ionic conductivity of the molten salt 3 KN03 · 2 Ca(NO3)2 has been measured at frequencies from 100 MHz to 40 GHz, at temperatures between 422 K and 478 K. Coaxial and rectangular waveguide systems have been used at 0.1 to 18 GHz and at 18 to 40 GHz, respectively. The conductivity is found to display the dispersion that is characteristic of the so-called “universal dielectric response". A similar dispersion was observed earlier at lower temperatures and frequencies. The data form arcs in the complex conductivity plane, with centers below the real axis. The modulus representation turns out to be comparatively involved and indirect, M″ featuring two maxima, while the conductivity data traverse a single arc in the complex plane. The present results are interpreted in terms o|f a non-Debye jump-relaxation model involving only one reorientational relaxation time. This time and its temperature dependence are close to those derived from other techniques.