Therapeutic drug monitoring of adalimumab in inflammatory bowel disease patients

OBJECTIVE: Adalimumab (ADA) trough levels correlate with clinical remission. Despite suggestions that therapeutic drug monitoring of ADA can optimize treatment in this population, it is not yet implemented in clinical practice. This study was conducted to provide more insight in ADA trough levels and antibodies to adalimumab (ATA) in an inflammatory bowel disease (IBD) population already treated with adalimumab. DESIGN: We carried out a prospective cohort study in IBD outpatients already treated with adalimumab. METHODS: Patient demographics were collected from the electronic hospital information system. Blood was drawn for determination of ADA trough levels and ATAs. Disease activity indices for Crohn's disease and ulcerative colitis and quality of life scores were obtained by a questionnaire. RESULTS: A total of 92 patients was included. ADA levels varied from &lt; 0.1 to 20.2 mg/L. Mean ADA level was 7.7 mg/L (SD = 4.5), 4 patients developed ATAs. ADA levels ≤ 5 mg/L were demonstrated in 27 patients (29%). The ADA level was not significantly associated with remission [P = 0.391). Quality of life score correlated with ADA level (P = 0.031). CONCLUSION: Therapeutic drug monitoring in inflammatory bowel disease outpatients revealed large interindividual differences in adalimumab trough levels. These levels were subtherapeutic in nearly a third of patients. We think, despite no significant correlation was found between adalimumab trough level and disease activity, therapeutic drug monitoring has the potential to individualize treatment in inflammatory bowel disease patients using adalimumab.</p

Therapeutic drug monitoring of adalimumab in inflammatory bowel disease patients

OBJECTIVE: Adalimumab (ADA) trough levels correlate with clinical remission. Despite suggestions that therapeutic drug monitoring of ADA can optimize treatment in this population, it is not yet implemented in clinical practice. This study was conducted to provide more insight in ADA trough levels and antibodies to adalimumab (ATA) in an inflammatory bowel disease (IBD) population already treated with adalimumab. DESIGN: We carried out a prospective cohort study in IBD outpatients already treated with adalimumab. METHODS: Patient demographics were collected from the electronic hospital information system. Blood was drawn for determination of ADA trough levels and ATAs. Disease activity indices for Crohn's disease and ulcerative colitis and quality of life scores were obtained by a questionnaire. RESULTS: A total of 92 patients was included. ADA levels varied from &lt; 0.1 to 20.2 mg/L. Mean ADA level was 7.7 mg/L (SD = 4.5), 4 patients developed ATAs. ADA levels ≤ 5 mg/L were demonstrated in 27 patients (29%). The ADA level was not significantly associated with remission [P = 0.391). Quality of life score correlated with ADA level (P = 0.031). CONCLUSION: Therapeutic drug monitoring in inflammatory bowel disease outpatients revealed large interindividual differences in adalimumab trough levels. These levels were subtherapeutic in nearly a third of patients. We think, despite no significant correlation was found between adalimumab trough level and disease activity, therapeutic drug monitoring has the potential to individualize treatment in inflammatory bowel disease patients using adalimumab.</p

Assessment of allelic diversity in intron-containing Mal d 1 genes and their association to apple allergenicity

<p>Abstract</p> <p>Background</p> <p>Mal d 1 is a major apple allergen causing food allergic symptoms of the oral allergy syndrome (OAS) in birch-pollen sensitised patients. The <it>Mal d 1 </it>gene family is known to have at least 7 intron-containing and 11 intronless members that have been mapped in clusters on three linkage groups. In this study, the allelic diversity of the seven intron-containing <it>Mal d 1 </it>genes was assessed among a set of apple cultivars by sequencing or indirectly through pedigree genotyping. Protein variant constitutions were subsequently compared with <b>S</b>kin <b>P</b>rick <b>T</b>est (SPT) responses to study the association of deduced protein variants with allergenicity in a set of 14 cultivars.</p> <p>Results</p> <p>From the seven intron-containing <it>Mal d 1 </it>genes investigated, <it>Mal d 1.01 </it>and <it>Mal d 1.02 </it>were highly conserved, as nine out of ten cultivars coded for the same protein variant, while only one cultivar coded for a second variant. <it>Mal d 1.04</it>, <it>Mal d 1.05 </it>and <it>Mal d 1.06 A, B </it>and <it>C </it>were more variable, coding for three to six different protein variants. Comparison of <it>Mal d 1 </it>allelic composition between the high-allergenic cultivar Golden Delicious and the low-allergenic cultivars Santana and Priscilla, which are linked in pedigree, showed an association between the protein variants coded by the <it>Mal d 1.04 </it>and <it>-1.06A </it>genes (both located on linkage group 16) with allergenicity. This association was confirmed in 10 other cultivars. In addition, <it>Mal d 1.06A </it>allele dosage effects associated with the degree of allergenicity based on prick to prick testing. Conversely, no associations were observed for the protein variants coded by the <it>Mal d 1.01 </it>(on linkage group 13), -<it>1.02</it>, -<it>1.06B, -1.06C </it>genes (all on linkage group 16), nor by the <it>Mal d 1.05 </it>gene (on linkage group 6).</p> <p>Conclusion</p> <p>Protein variant compositions of Mal d 1.04 and -1.06A and, in case of <it>Mal d 1.06A</it>, allele doses are associated with the differences in allergenicity among fourteen apple cultivars. This information indicates the involvement of qualitative as well as quantitative factors in allergenicity and warrants further research in the relative importance of quantitative and qualitative aspects of <it>Mal d 1 </it>gene expression on allergenicity. Results from this study have implications for medical diagnostics, immunotherapy, clinical research and breeding schemes for new hypo-allergenic cultivars.</p

Content-based recommender support system for counselors in a suicide prevention chat helpline: Design and evaluation study

Background: The working environment of a suicide prevention helpline requires high emotional and cognitive awareness from chat counselors. A shared opinion among counselors is that as a chat conversation becomes more difficult, it takes more effort and a longer amount of time to compose a response, which, in turn, can lead to writer's block. Objective: This study evaluates and then designs supportive technology to determine if a support system that provides inspiration can help counselors resolve writer's block when they encounter difficult situations in chats with help-seekers. Methods: A content-based recommender system with sentence embedding was used to search a chat corpus for similar chat situations. The system showed a counselor the most similar parts of former chat conversations so that the counselor would be able to use approaches previously taken by their colleagues as inspiration. In a within-subject experiment, counselors' chat replies when confronted with a difficult situation were analyzed to determine if experts could see a noticeable difference in chat replies that were obtained in 3 conditions: (1) with the help of the support system, (2) with written advice from a senior counselor, or (3) when receiving no help. In addition, the system's utility and usability were measured, and the validity of the algorithm was examined. Results: A total of 24 counselors used a prototype of the support system; the results showed that, by reading chat replies, experts were able to significantly predict if counselors had received help from the support system or from a senior counselor (P=.004). Counselors scored the information they received from a senior counselor (M=1.46, SD 1.91) as significantly more helpful than the information received from the support system or when no help was given at all (M=-0.21, SD 2.26). Finally, compared with randomly selected former chat conversations, counselors rated the ones identified by the content-based recommendation system as significantly more similar to their current chats (β=.30, P<.001). Conclusions: Support given to counselors influenced how they responded in difficult conversations. However, the higher utility scores given for the advice from senior counselors seem to indicate that specific actionable instructions are preferred. We expect that these findings will be beneficial for developing a system that can use similar chat situations to generate advice in a descriptive style, hence helping counselors through writer's block

FAM222B Is Not a Likely Novel Candidate Gene for Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are prevalent slow-flow vascular lesions which harbour the risk to develop intracranial haemorrhages, focal neurological deficits, and epileptic seizures. Autosomal dominantly inherited CCMs were found to be associated with heterozygous inactivating mutations in 3 genes, CCM1(KRIT1), CCM2(MGC4607), and CCM3(PDCD10) in 1999, 2003 and 2005, respectively. Despite the availability of high-throughput sequencing techniques, no further CCM gene has been published since. Here, we report on the identification of an autosomal dominantly inherited frameshift mutation in a gene of thus far unknown function, FAM222B(C17orf63), through exome sequencing of CCM patients mutation-negative for CCM1-3. A yeast 2-hybrid screen revealed interactions of FAM222B with the tubulin cytoskeleton and STAMBP which is known to be associated with microcephaly-capillary malformation syndrome. However, a phenotype similar to existing models was not found, neither in fam222bb/fam222ba double mutant zebrafish generated by transcription activator-like effector nucleases nor in an in vitro sprouting assay using human umbilical vein endothelial cells transfected with siRNA against FAM222B. These observations led to the assumption that aberrant FAM222B is not involved in the formation of CCMs

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

Assessing the legitimacy of flood risk governance arrangements in Europe: insights from intra-country evaluations

Legitimacy has received comparatively less attention than societal resilience in the context of flooding, thus methods for assessing and monitoring the legitimacy of Flood Risk Governance Arrangements (FRGA) are noticeably lacking. This study attempts to address this gap by assessing the legitimacy of FRGAs in six European countries through cross-disciplinary and comparative research methods. On the basis of this assessment, recommendation