Underexposed features of CHARGE syndrome: immunological, adrenal, and scapular function

CHARGE syndrome is a rare and complex genetic condition. Children with this syndrome may have a combination of various congenital defects, developmental and behavioral problems. Abnormalities such as heart defects, blindness or deafness, receive a lot of attention. This is certainly important, but in this thesis we have focused on less obvious features: the immune system, the adrenal and shoulder function. Our studies show that children with CHARGE syndrome may have a reduced immune reaction to infections because they have insufficient immune cells. They also have an insufficient response to vaccinations. The thymus is an important organ for the production of immune cells, but we could not confirm in what extent the thymus might play a role in our findings. We have demonstrated that abnormalities in the adrenal function rarely occur. We also showed that reduced shoulder function, due to abnormalities in the nerves innervating the muscles, could be the only visible sign of CHARGE syndrome. The results of our research should be included in current guideline(s) to create more awareness among doctors so that patients can receive optimal care, also for underexposed features. For example, we advise to do specific blood tests and to consider revaccinations in patients who have recurrent infections. Standard testing for the adrenal function is not required which may give patients and their parents some relief. The thesis ends with a message on how important it is that patients, doctors, researchers and policy makers work together to tackle underexposed issues in rare diseases

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Typologies of Lexicalization Patterns and Event Integration:Clarifications and Reformulations

textabstractCHARGE syndrome is a variable, multiple congenital malformation syndrome. Patients with CHARGE syndrome have frequent infections that are presumed to be due to anatomical anomalies of the craniofacial region and upper airway, and cranial nerve problems resulting in swallowing difficulties and aspiration. The possible contribution of immunological abnormalities to these infections has not been systematically studied even though immune deficiencies have been described in patients with 22q11.2 deletion syndrome, a condition which shares remarkable clinical overlap with CHARGE syndrome. We assessed the frequency and nature of immune dysfunction in 24 children with genetically proven CHARGE syndrome. All patients, or their parents, completed a questionnaire on infectious history. Their immune system was extensively assessed through full blood counts, immunoglobulin levels, lymphocyte subpopulations, peripheral B-and T-cell differentiation, T-receptor excision circle (TREC) analysis, T-cell function, and vaccination responses. All CHARGE patients had a history of infections (often frequent), mainly otitis media and pneumonia, leading to frequent use of antibiotics and to hospital admissions. Decreased T-cell numbers were found in 12 (50%) patients, presumably caused by insufficient thymic output since TREC amounts were also diminished in CHARGE patients. Despite normal peripheral B-cell differentiation and immunoglobulin production in all patients, 83% of patients had insufficient antibody titers to one or more early childhood vaccinations. Based on our results, we recommend immunological evaluation of CHARGE patients with recurrent infections