The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.
Aim: To assess occlusal outcomes of orthodontic treatment for patients with complete cleft lip and palate. Design: Retrospective assessment using the Peer Assessment Rating (PAR) index. Setting: Consecutive patients treated by one consultant orthodontist at a tertiary care cleft center. Participants: One hundred twenty-seven patients with either complete unilateral cleft lip and palate (UCLP) or bilateral cleft lip and palate (BCLP) consecutively treated with fixed appliances. Intervention: Fixed orthodontic appliance treatment and orthognathic surgery when required. Outcomes: The PAR index assessment was carried out by a calibrated-independent assessor. Treatment duration, the number of patient visits, and data on dental anomalies were drawn from patient records and radiographs. Results: One hundred two patients’ study models were assessed after exclusions. Mean start PAR score for UCLP (n = 71) was 43.9 (95% CI, 41.2-46.6, SD 11.5), with a mean score reduction of 84.3% (95% CI, 81.9-86.7, SD 10.1). The UCLP mean treatment time was 23.7 months with 20.1 appointments. Mean start PAR score for BCLP (n = 31) was 43.4 (95% CI, 39.2-47.6, SD 11.4), with a mean score reduction of 80.9% (95% CI, 76.3-85.5, SD 12.5). The BCLP mean treatment time was 27.8 months with 20.5 appointments. Conclusion: These results compare well with other outcome reports, including those for patients without a cleft, and reflect the standard of care provided by an experienced cleft orthodontist. As with high-volume surgeons, orthodontic treatment for this high need group is favorable when provided by a high-volume orthodontist. These findings may be used for comparative audit with similar units providing cleft care.
Summary Background At the clinical trial design stage, assumptions regarding the treatment effects to be detected should be appropriate so that the required sample size can be calculated. There is evidence in the medical literature that sample size assumption can be overoptimistic. The aim of this study was to compare the distribution of the assumed effects versus that of the observed effects as a proxy for overoptimistic treatment effect assumptions at the study design stage. Materials and method Systematic reviews (SRs) published between 1 January 2010 and 31 December 2019 containing at least one meta-analysis on continuous outcomes were identified electronically. SR and primary study level characteristics were extracted from the SRs and the individual trials. Details on the sample size calculation process and assumptions and the observed treatment effects were extracted. Results Eighty-five SRs with meta-analysis containing 347 primary trials were included. The median number of SR authors was 5 (interquartile range: 4–7). At the primary study level, the majority were single centre (78.1%), utilized a parallel design (52%), and rated as an unclear/moderate level of risk of bias (34.3%). A sample size was described in only 31.7% (110/347) of studies. From this cohort of 110 studies, in only 37 studies was the assumed clinical difference that the study was designed to detect reported (37/110). The assumed treatment effect was recalculated for the remaining 73 studies (73/110). The one-sided exact signed rank test showed a significant difference between the assumed and observed treatment effects (P < 0.001) suggesting greater values for the assumed effect sizes. Conclusions Careful consideration of the assumptions at the design stage of orthodontic studies are necessary in order to reduce the unreliability of clinical study results and research waste.
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