Further validation in animal models and trials in humans are needed

The current work is presented as a proof-of-concept study, without direct translation for clinical development. Still, we think that HLE anti-rabies VHH have the potential to be used as an alternative to RIG or monoclonal antibodies to provide passive immunity after risk exposure. Of course, further validation in animal models and trials in humans are needed to enforce this, as the current study design and animal model does not allow validation of VHH for post exposure prophylaxis in humans. Rabies virus-exposed patients are currently treated with RIG and vaccine soon after exposure. Patients receive RIG and vaccine on day 0 and additional vaccine shots in the following weeks. The rationale is that patients need continued protection by anti-rabies antibodies starting as soon as possible after exposure. First protection is offered by passively acquired antibodies, which are then gradually replaced by vaccine-induced antibodies. In some studies, the reference standard is the presence of any notation of an HF diagnosis in the medical chart, and cases are classified simply as HF or no HF. The Framingham criteria also classify cases as either HF or no HF; at least two of the major Framingham criteria or one major criterion and two minor criteria must be met for the diagnosis of HF. Other sets of standard criteria do allow for further classification. The Carlson criteria use a points Climbazole system in which potential cases are evaluated in three categories, and allocated a maximum of four points in each category, and a maximum overall score of 12. A score of 8 or more is considered Definite HF while 5�C7 points are considered Possible HF, and 4 or fewer points are classified as Unlikely HF. Under the European Society of Cardiology criteria, for a case to be classified as HF there must be both signs and symptoms of HF, and objective evidence of cardiac dysfunction. Some investigators have classified cases meeting both of these criteria as Definite HF, and those meeting only one of these criteria as Questionable, Possible, or Probable HF. It should be noted that while the New York Heart Association functional classification is used to measure the degree of functional limitation experienced by HF patients, and may assist in the selection of therapies, it is not used to make the initial diagnosis of HF. Taken together, these data suggest that the fusion events we identified are unlikely to be due to artifactual transsplicing events during RNA-Seq library preparation and thus represent bona-fide fusions of genomic or transcriptomic origin. We do acknowledge that the TaqMan assays can tolerate a few Pyridoxine hydrochloride single nucleotide variants within the assayed amplicons and, while we think it is unlikely, it is conceivable that some of the identified fusion transcripts are not accurate. Here we have observed a substantially higher percentage of intronic reads than what have been reported in many studies using fresh tissue RNA.

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