Role of primary cilia and Hedgehog signaling in craniofacial features of Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is an autosomal recessive genetic disorder involving pathogenic variants of EVC and EVC2 genes and classified as a ciliopathy. The syndrome is caused by mutations in the EVC gene on chromosome 4p16, and EVC2 gene, located close to the EVC gene, in a head-to-head configuration. Regardless of the affliction of EVC or EVC2, the clinical features of Ellis-van Creveld syndrome are similar. Both these genes are expressed in tissues such as, but not limited to, the heart, liver, skeletal muscle, and placenta, while the predominant expression in the craniofacial tissues is that of EVC2. Biallelic mutations of EVC and EVC2 affect Hedgehog signaling and thereby ciliary function, crucial factors in vertebrate development, culminating in the phenotypical features characteristic of EvC. The clinical features of Ellis-van Creveld syndrome are consistent with significant abnormalities in morphogenesis and differentiation of the affected tissues. The robust role of primary cilia in histodifferentiation and morphodifferentiation of oral, perioral, and craniofacial tissues is becoming more evident in the most recent literature. In this review, we give a summary of the mechanistic role of primary cilia in craniofacial development, taking Ellis-van Creveld syndrome as a representative example.

A Comparative Analysis of Follicular Diameter Assessment Versus Doppler Ultrasound in Predicting Ovulation Timing for the Infertility Treatment: Insights From a Prospective Study.

Background Infertility remains a significant challenge affecting millions of couples worldwide, with ovulation abnormalities being a common underlying cause. Pharmacological methods, such as clomiphene citrate, are often used to stimulate ovulation. However, the optimal timing for sexual intercourse during ovulation induction remains contentious. Objectives This study aimed to compare the efficacy of transvaginal ultrasonography (TVS) for measuring follicle size with Doppler ultrasound for assessing changes in blood flow to predict the timing of ovulation. Methods We conducted a comparative analysis involving 64 women undergoing infertility therapy. Participants were evaluated using both TVS to measure follicle diameter and Doppler ultrasound to assess perifollicular blood flow dynamics. The primary outcomes measured included ovulation rates, resistive index (RI) values, peak systolic velocity (PSV) values, and conception rates. Results The analysis showed comparable age distributions between the TVS and Doppler groups. There was no significant correlation between follicle diameter and ovulation when assessed by TVS. However, Doppler ultrasound revealed a substantial association between perifollicular blood flow dynamics and ovulation. Higher ovulation rates were linked to lower RI values and higher PSV values, indicating their potential as predictors of ovulation. Additionally, higher conception rates were positively correlated with increased vascularity in Zone 4 of the endometrium. Conclusion Doppler ultrasonography indices, particularly RI and PSV values, provide critical insights into perifollicular blood flow dynamics and endometrial vascularity, which can enhance the effectiveness of fertility treatments. While these findings highlight the potential of Doppler ultrasound in predicting ovulation and improving treatment outcomes, further research is required to understand the underlying mechanisms and validate these results for personalised treatment strategies.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).