Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved

Anti-IgE treatment in allergic rhinitis

WOS: 000500653300004PubMed: 31526939Objectives: To review the efficacy of anti-IgE therapy in allergic rhinitis (AR). Methods: Literature search was performed using the PubMed and Proquest Central databases at Kirikkale University Library. Results: Although the skin prick testing in patients suffering from AR is positive (indicating that antigen-specific Immunoglobulin E has been produced), there is no association with overall circulating IgE levels. Correlation was lacking between circulating IgE level and either skin prick tests or laboratory testing for specific IgE. Omalizumab binds to uncomplexed IgE in man more avidly than does Fc-epsilon. The effect of omalizumab is to lower the level of IgE and downgrade production of FceRI receptors (which bind IgE) in mast cells and basophils, causing less mast cell recruitment and responsivity and thus diminishing eosinophilic infiltration and activation. Anti-IgE therapy through omalizumab may shorten the lifetime of mast cells and causes dendritic cells to downgrade their production of FceRI. There are reports indicating benefit from omalizumab in managing food allergies, nasal polyp formation, essential anaphylaxis, AR, venom allergy and eczema. Omalizumab acts to lessen circulating IgE levels, whilst reducing production of FceRI by mast cells and basophils. The fact that omalizumab influences how eosinophils respond may be down to disruption of the antigen-IgE-mast cell interactions, with mast cells being recruited at lower levels and thus chemotactic eosinophilic recruitment via cytokines being greatly reduced. Omalizumab has the effect in cases of perennial AR of blocking the increased eosinophilic recruitment and tissue infiltration initiated by seasonal antigens. Likewise, in omalizumab-treated cases, circulating unbound IgE levels showed significant decreases. For patients with perennial AR, the average daily nasal severity score was significantly reduced where omalizumab was administered, compared to placebo. Conclusion: Omalizumab has efficacy in ameliorating symptoms and reduces the necessity for additional medication in both seasonal and perennial allergic rhinitisContinuous Education and Scientific Research AssociationWith the exception of the data collection, the preparation of this paper, including design and planning, was supported by the Continuous Education and Scientific Research Association. Support was scientific rather than financial

Success rates for various graft materials in tympanoplasty – A review

Objectives: The aim of this paper is to review how successful each type of grafts is in tympanoplasty. Methods: Pubmed, Google and the Proquest Central Database at Kırıkkale University were queried using the keywords “graft”, “success” “tympanoplasty”, “success rate” with the search limited to the period 1955 to 2017. Results: Various types of graft materials including temporalis fascia, cartilage, perichondrium, periosteum, vein, fat or skin have been used in the reconstruction of tympanic membrane (TM) perforation. Although temporalis fascia ensures good hearing is restored, there are significant concerns that its dimensional stability characteristics may lead to residual perforation, especially where large TM perforations are involved. The “palisade cartilage” and “cartilage island” techniques have been stated to increase the strength and stability of a tympanic graft, but they may result in a less functional outcome in terms of restoring hearing. Smoking habits, the size and site of a perforation, the expertise level of the operating surgeon, age, gender, the status of the middle ear mucosa and the presence of myringosclerosis or tympanosclerosis are all important in determining how successful a graft is. Conclusion: Although temporal fascia is the most commonly used graft material for tympanoplasty, poor graft stability may cause failure. This failure is due to the inclusion of connective fibrous tissue containing irregular elastic fibers present in the grafted fascia. Cartilage grafts offer better ability to resist infection, pressure, and cope with insufficient vascular supply. This means that cartilage grafts are suitable for use in revision cases. © 2020 PLA General Hospital Department of Otolaryngology Head and Neck SurgeryWith exception of data collection, preparation of this paper including design and planning was supported by Continuous Education and Scientific Research Association

Consensus on Methodology for Experimental Studies of Nasal Mucosal Injury

PubMed: 31449221Objectives:The way wounds heal involves significant complexity, resulting in restoration of functional and anatomical integrity to tissues damaged as a result of trauma (whether mechanical, chemical, or radiation-induced). The authors reviewed the consensus on methodology for experimental studies of nasal mucosal injury.Methods:The review aims to find where consensus exists amongst different experimental studies in nasal wound healing about the use of animal models. To achieve this, the authors queried the Pubmed, Proquest Central and Google databases for the last 20 years (i.e. 1996-2016). The search terms were: "mucosa injury," "nasal mucosa injury," "injury," "wound healing," "nasal," "nasal wound healing," "experimental," "animal," "model," "rat," "rabbit," "guinea pig," and "mice." These terms were searched for whether they occurred singly or in combination. The search uncovered 18 papers, on the basis of which this review has been prepared.Results:The choice of an appropriate animal model is key in investigating nasal mucosal injury. Suitable animals include rodents such as rats or guinea pigs. There are reports in the literature concerning mechanical injury in rat nasal mucosae without attempts to treat it. Mechanical injury was induced unilaterally by means of an interdental brush. Other techniques involved the use of distilled water or irradiating the tissue to induce trauma.Conclusion:In this review, the use of a rat, guinea pig or rabbit model for human nasal mucosal injury is reviewed. Such models are suitable for use in well-designed experimental studies. © 2019 by Mutaz B. Habal, MD