Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine

Background: GATA transcription factors are essential for self-renewal of the small intestinal epithelium. Gata4 is expressed in the proximal 85% of small intestine while Gata6 is expressed throughout the length of small intestine. Deletion of intestinal Gata4 and Gata6 results in an altered proliferation/differentiation phenotype, and an up-regulation of SAM pointed domain containing ETS transcription factor (Spdef), a transcription factor recently shown to act as a tumor suppressor. The goal of this study is to determine to what extent SPDEF mediates the downstream functions of GATA4/GATA6 in the small intestine. The hypothesis to be tested is that intestinal GATA4/GATA6 functions through SPDEF by repressing Spdef gene expression. To test this hypothesis, we defined the functions most likely regulated by the overlapping GATA6/SPDEF target gene set in mouse intestine, delineated the relationship between GATA6 chromatin occupancy and Spdef gene regulation in Caco-2 cells, and determined the extent to which prevention of Spdef up-regulation by Spdef knockout rescues the GATA6 phenotype in conditional Gata6 knockout mouse ileum. Results: Using publicly available profiling data, we found that 83% of GATA6-regulated genes are also regulated by SPDEF, and that proliferation/cancer is the function most likely to be modulated by this overlapping gene set. In human Caco-2 cells, GATA6 knockdown results in an up-regulation of Spdef gene expression, modeling our mouse Gata6 knockout data. GATA6 occupies a genetic locus located 40 kb upstream of the Spdef transcription start site, consistent with direct regulation of Spdef gene expression by GATA6. Prevention of Spdef up-regulation in conditional Gata6 knockout mouse ileum by the additional deletion of Spdef rescued the crypt cell proliferation defect, but had little effect on altered lineage differentiation or absorptive enterocytes gene expression. Conclusion: SPDEF is a key, immediate downstream effecter of the crypt cell proliferation function of GATA4/GATA6 in the small intestine

Evaluating (inter)national variations of cochlear implantation in children : Towards evidence-based practice uniformity for cochlear implantation in children

Substantial evidence shows that cochlear implantation is the preferred treatment for infants presenting with severe to profound hearing loss. However, the sensitive period of neurolinguistic development varies between speech and language domains, and therefore, determining the ideal timing for cochlear implantation based on these time frames remains difficult and has not yet been strictly defined. Furthermore, differences between cochlear implant manufacturers’ and national cochlear implant guidelines exist regarding paediatric cochlear implant candidacy eligibility criteria. Since no uniform indication criteria currently exist, this dissertation formulates an evidence-based guideline for cochlear implantation in children. Definition of uniform indication criteria and a structured timeline of the selection process of pediatric cochlear implant cadidates can help parents understand both clinical processes and thus prevent delay in care. Through three literature studies and four retrospective studies, data were gathered to formulate evidence-based guidelines. Based on our findings, we recommend that children with prelingual hearing loss, without serious co-morbidity, undergo cochlear implantation if: 1. They are between 12 and 18 months old, based on four speech and language domains (speech perception and production, receptive language development and auditory performance) 2. They present with hearing loss of ≥ 80 decibels (2-frequency Pure Tone Average thresholds of ≥ 85 decibels of hearing loss or 4-frequency Pure Tone Average thresholds of ≥ 80 decibels of hearing loss) 3. The mastoidectomy with posterior tympanotomy technique is used peroperatively. In terms of anesthetic technique, both intravenous propofol and sevoflurane (inhalation) gas can be used. In our international assessment, we found that only 30% of the European pediatric population was implanted before the age of 24 months. This delay in care provision is remarkable and can be shortened in the future by: more optimal compliance with already implemented guidelines, improved alignment between international guidelines and more awareness among parents of the impact of hearing loss for their child. Through our evidence-based advice we hope to reduce variation from clinician to clinician. In the future, we expect that by providing information via telemedicine (e.g., the application of mobile applications), parents better understand the indication criteria and the timeline of the candidate selection and delay in auditory rehabilitation can be prevented

Evaluating (inter)national variations of cochlear implantation in children : Towards evidence-based practice uniformity for cochlear implantation in children

Substantial evidence shows that cochlear implantation is the preferred treatment for infants presenting with severe to profound hearing loss. However, the sensitive period of neurolinguistic development varies between speech and language domains, and therefore, determining the ideal timing for cochlear implantation based on these time frames remains difficult and has not yet been strictly defined. Furthermore, differences between cochlear implant manufacturers’ and national cochlear implant guidelines exist regarding paediatric cochlear implant candidacy eligibility criteria. Since no uniform indication criteria currently exist, this dissertation formulates an evidence-based guideline for cochlear implantation in children. Definition of uniform indication criteria and a structured timeline of the selection process of pediatric cochlear implant cadidates can help parents understand both clinical processes and thus prevent delay in care. Through three literature studies and four retrospective studies, data were gathered to formulate evidence-based guidelines. Based on our findings, we recommend that children with prelingual hearing loss, without serious co-morbidity, undergo cochlear implantation if: 1. They are between 12 and 18 months old, based on four speech and language domains (speech perception and production, receptive language development and auditory performance) 2. They present with hearing loss of ≥ 80 decibels (2-frequency Pure Tone Average thresholds of ≥ 85 decibels of hearing loss or 4-frequency Pure Tone Average thresholds of ≥ 80 decibels of hearing loss) 3. The mastoidectomy with posterior tympanotomy technique is used peroperatively. In terms of anesthetic technique, both intravenous propofol and sevoflurane (inhalation) gas can be used. In our international assessment, we found that only 30% of the European pediatric population was implanted before the age of 24 months. This delay in care provision is remarkable and can be shortened in the future by: more optimal compliance with already implemented guidelines, improved alignment between international guidelines and more awareness among parents of the impact of hearing loss for their child. Through our evidence-based advice we hope to reduce variation from clinician to clinician. In the future, we expect that by providing information via telemedicine (e.g., the application of mobile applications), parents better understand the indication criteria and the timeline of the candidate selection and delay in auditory rehabilitation can be prevented

A Systematic Review to Define the Speech and Language Benefit of Early (<12 Months) Pediatric Cochlear Implantation

Objective: This review aimed to evaluate the additional benefit of pediatric cochlear implantation before 12 months of age considering improved speech and language development and auditory performance. Materials and Methods: We conducted a search in PubMed, EMBASE and CINAHL databases and included studies comparing groups with different ages at implantation and assessing speech perception and speech production, receptive language and/or auditory performance. We included studies with a high directness of evidence (DoE). Results: We retrieved 3,360 articles. Ten studies with a high DoE were included. Four articles with medium DoE were discussed in addition. Six studies compared infants implanted before 12 months with children implanted between 12 and 24 months. Follow-up ranged from 6 months to 9 years. Cochlear implantation before the age of 2 years is beneficial according to one speech perception score (phonetically balanced kindergarten combined with consonantnucleus- consonant) but not on Glendonald auditory screening procedure scores. Implantation before 12 months result-ed in better speech production (diagnostic evaluation of articulation and phonology and infant-toddler meaningful auditory integration scale), auditory performance (Categories of Auditory Performance-II score) and receptive language scores (2 out of 5; Preschool Language Scale combined with oral and written language skills and Peabody Picture Vocabulary Test). Conclusions: The current best evidence lacks level 1 evidence studies and consists mainly of cohort studies with a moderate to high risk of bias. Included studies showed consistent evidence that cochlear implantation should be performed early in life, but evidence is inconsistent on all speech and language outcome measures regarding the additional benefit of implantation before the age of 12 months. Long-term follow-up studies are necessary to provide insight on additional benefits of early pediatric cochlear implantation

Systematic Review on Surgical Outcomes and Hearing Preservation for Cochlear Implantation in Children and Adults

OBJECTIVE: The mastoidectomy with facial recess approach (MFRA) is considered the reference standard for cochlear implantation. The suprameatal approach (SMA) was developed more recently and does not require mastoidectomy, which could influence postoperative outcomes. We aim to identify the optimal operative approach for cochlear implantation based on postoperative complications and hearing preservation in children and adults. DATA SOURCES: PubMed, EMBASE, Scopus, and Google Scholar. REVIEW METHODS: Studies comparing MFRA and SMA in children and adults were eligible for inclusion. Original reports with moderate relevance and validity were included. Relevance and validity were assessed with a self-modified critical appraisal tool. This review was reported in accordance to PRISMA guidelines. RESULTS: We retrieved 294 citations. Only retrospective nonrandomized studies were identified (level III evidence). Six articles were selected for full-text inclusion and 4 articles for data extraction. No article found a significant difference between MFRA and SMA with respect to postoperative complications in children and adults. One study found a significantly (P < .023) higher pediatric MFRA mastoiditis rate; however, meta-analysis did not indicate an overall effect. Hearing preservation was reported only in adults, and outcomes between techniques did not differ. CONCLUSION: No evidence was noted for lower complication rates or improved hearing preservation between the MFRA and SMA for cochlear implantation in children and adults. Pediatric data were available for children implanted above the age of 24 months only. Level I evidence is needed to resolve the uncertainty regarding differences in postoperative outcomes of pediatric and adult MFRA and SMA

A systematic review on the surgical outcome of preauricular sinus excision techniques

Objectives/Hypothesis: Preauricular sinuses are benign congenital malformations of preauricular soft tissues. Complete excision using either sinectomy or supra-auricular approach is advised to prevent recurrence. Reported recurrence varies between 0 and 42%. We evaluated which surgical technique resulted in lowest complication and recurrence rates. Study Design: PubMed, Embase, Scopus, Web of Science. Methods: Two authors appraised studies on directness of evidence and risk of bias. Original data were extracted and pooled when I2 was smaller than 50%. Results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Results: Fourteen high directness of evidence studies were included. Reported complication rates were similar: sinectomy [0-31.4%] and supra-auricular approach (SAA) [0-18.2%]. Pooled recurrence rates showed that sinectomy resulted in significantly (P = .04) more recurrence 5.5% (95% confidence interval [CI] 3.6-8.3%) than SAA 2.2% (95% CI 0.7-7.0). Sinectomy using the microscope resulted in the lowest sinectomy recurrence rates (1.9%). SAA in combination with a Penrose drain resulted in 0% recurrence in revision cases. Drain use resulted in the lowest SAA recurrence rates; however, drain application was not advised due to higher complication rates (frequent wound infection [P = .003] and more [P = .002] and longer [P = .001] compression dressing use). Conclusion: SAA could be the preferable technique for preauricular sinus removal. If despite evidence, sinectomy is elected over SAA, microscope use can further decrease recurrence rates comparable to SAA levels. Level of included evidence (Ib-IV) indicates the need for a prospective study comparing surgical outcomes between techniques