Quantitative Field Emission Imaging for Studying the Doping-Dependent Emission Behavior of Silicon Field Emitter Arrays.

Field emitter arrays (FEAs) are a promising component for novel vacuum micro- and nanoelectronic devices, such as microwave power amplifiers or fast-switching X-ray sources. However, the interrelated mechanisms responsible for FEA degradation and failure are not fully understood. Therefore, we present a measurement method for quantitative observation of individual emission sites during integral operation using a low-cost, commercially available CMOS imaging sensor. The emission and degradation behavior of three differently doped FEAs is investigated in current-regulated operation. The measurements reveal that the limited current of the p-doped emitters leads to an activation of up to 55% of the individual tips in the array, while the activation of the n-type FEA stopped at around 30%. This enhanced activation results in a more continuous and uniform current distribution for the p-type FEA. An analysis of the individual emitter characteristics before and after a constant current measurement provides novel perspectives on degradation behavior. A burn-in process that trims the emitting tips to an integral current-specific ideal field enhancement factor is observed. In this process, blunt tips are sharpened while sharp tips are dulled, resulting in homogenization within the FEA. The methodology is described in detail, making it easily adaptable for other groups to apply in the further development of promising FEAs.

A Robust Miniaturized Gas Sensor for H2 and CO2 Detection Based on the 3ω Method.

Gas concentration monitoring is essential in industrial or life science areas in order to address safety-relevant or process-related questions. Many of the sensors used in this context are based on the principle of thermal conductivity. The 3ω-method is a very accurate method to determine the thermal properties of materials. It has its origin in the thermal characterization of thin solid films. To date, there have been very few scientific investigations using this method to determine the thermal properties of gases and to apply it to gas measurement technology. In this article, we use two exemplary gases (H2 and CO2) for a systematical investigation of this method in the context of gas analysis. To perform our experiments, we use a robust, reliable sensing element that is already well established in vacuum measurement technology. This helix-shaped thin wire of tungsten exhibits high robustness against chemical and mechanical influences. Our setup features a compact measurement environment, where sensor operation and data acquisition are integrated into a single device. The experimental results show a good agreement with a simplified analytical model and FEM simulations. The sensor exhibits a lower detection limit of 0.62% in the case of CO2, and only 0.062% in case the of H2 at an excitation frequency of 1 Hz. This is one of the lowest values reported in literature for thermal conductivity H2 sensors.

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn's Disease.

BACKGROUND & AIMS: The pathogenesis of chronic inflammatory bowel diseases (Crohn's disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined. METHODS: Lymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro. RESULTS: TFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo. CONCLUSIONS: These data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients.

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn's disease - a regional multi-center pilot study.

BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.

Development of a Mass Spectrometry-Based Method for Quantification of Ustekinumab in Serum Specimens.

BACKGROUND: Ustekinumab (UST) is a human monoclonal antibody used to treat moderate-to-severe Crohn disease by blocking the interleukin-12/23 pathway. Although an optimized therapeutic concentration of UST is associated with clinical response and improved prognosis, the availability of clinical laboratory methods for UST monitoring is limited. Furthermore, the commercially available methods are immunoassays that are prone to interference of antidrug antibodies. This study aimed to develop a liquid chromatography-tandem mass spectrometry method for quantification of UST in human serum specimens. METHODS: A tryptic peptide that is specific to the heavy chain variable region of UST was selected. Quantification of UST was performed by selective reaction monitoring on a quadrupole TQ-XS with an internal standard. After digestion with trypsin, peptides were separated by reverse-phase C18 liquid chromatography; peptides were detected by MS/MS, and analyte to internal standard peak area ratios were used for the quantification. Finally, serum samples from patients treated with UST were collected at trough levels (n = 66). RESULTS: The assay showed a broad dynamic range with linearity between 0.4 and 20 mg/L (R = 0.995). The lower limit of quantification was found to be 0.4 mg/L. The reproducibility was tested with 3 different UST concentrations (2, 8, and 16 mg/L). The coefficients of intra-assay and interassay variations were 2.2%-4.0% and 2.7%-5.3%, respectively. UST serum concentrations of 2-16 mg/L were stable for up to 14 days when specimens were left at room temperature (20°C). CONCLUSIONS: The newly developed LC/MS-based method was shown to be feasible for UST quantification. This analytical approach may lead to individualized dosing and improved patient care.

Detecting Anti-IIa and Anti-Xa Direct Oral Anticoagulant (DOAC) Agents in Urine using a DOAC Dipstick.

The assessment of the anticoagulant effect of direct oral anticoagulants (DOACs) can be important for rapid medical decision-making, especially in patients needing immediate management. An assay that screens for the absence or presence of a DOAC would help accelerate treatment in these situations. Chromogenic and coagulation methods have several limitations, including limited accuracy, long turnaround time, and their need of specialized laboratories. Oral factor Xa and thrombin inhibitors are also eliminated by the kidneys and can be detected in patient urine samples using a single, rapid, sensitive, and patient-specific qualitative assay. In these tests, the presence or absence of a DOAC in urine can be identified by visually observing specific colors after a few minutes. Several studies have demonstrated the robustness and repeatability of these assays. The specific colors of the test strip also detect creatinine in the urine, which shows whether DOAC excretion is reduced, thus suggesting renal impairment. Persons with amblyopia may use a specific reader. Current indications for using the DOAC Dipstick test include emergency medical situations with severe bleeding and thrombotic events or before urgent major surgical interventions to accelerate medical decision-making.

Pregabalin abuse among opiate addicted patients.

PURPOSE: Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. METHODS: Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. RESULTS: We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. CONCLUSIONS: Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.

Green tea halts progression of cardiac transthyretin amyloidosis: an observational report.

BACKGROUND: Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a single-center observational report on the effects of GT consumption in patients with ATTR cardiomopathy. METHODS: 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months. RESULTS: Five patients were not followed up for reasons of death (n = 2), discontinuation of GT/GTE consumption (n = 2), and heart transplantation (n = 1). After 12 months no increase of left ventricular (LV) wall thickness and LV myocardial mass was observed by echocardiography. In the subgroup of patients evaluated by cardiac MRI a mean decrease of LV myocardial mass (-12.5 %) was detected in all patients. This was accompanied by an increase of mean mitral annular systolic velocity of 9 % in all 14 patients. Total cholesterol (191.9 ± 8.9 vs. 172.7 ± 9.4 mg/dL; p < 0.01) and LDL cholesterol (105.8 ± 7.6 vs. 89.5 ± 8.0 mg/dL; p < 0.01) decreased significantly during the observational period. No serious adverse effects were reported by any of the participants. CONCLUSIONS: Our observation suggests an inhibitory effect of GT and/or GTE on the progression of cardiac amyloidosis. We propose a randomized placebo-controlled investigation to confirm our observation.