Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (¹⁰B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of ¹⁰B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of ¹⁰B in a specific tissue in real-time using noninvasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. Moreover, functional imaging technologies such as PET can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Anyway, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment.

Genetic sensorineural hearing loss and Meniere disease have been associated with rare variations in the coding and non-coding region of the human genome. Most of these variants are classified as likely pathogenic or variants of unknown significance and require functional validation in cellular or animal models. Given the difficulties to obtain human samples and the raising concerns about animal experimentation, human induced pluripotent stem cells emerge as cellular models to investigate the interaction of genetic and environmental factors in the pathogenesis of inner ear disorders. The generation of human sensory epithelia and neuron-like cells carrying the variants of interest may facilitate a better understanding of their role during differentiation. These cellular models will allow us to explore new strategies for restoring hearing and vestibular sensory epithelia as well as neurons. This review summarizes the use of human induced pluripotent stem cells in sensorineural hearing loss and Meniere disease and proposes some strategies for its application in clinical practice.

Objective: The purpose of the present study was to analyze the management of dental extractions in patients affected by coagulation disorders in order to prevent bleeding intraoperative and postoperative complications. Subjects and Methods: This study included 17 patients with a diagnosis of a coagulation disorder, who had been subjected to a single or multiple dental extraction. Recombinant activated Factor VII was administered in those patients who were affected by a deficit of factor VII ranged between 10,5% and 21%. The other patients were treated locally with tranexamic acid. Results: A total of 50 teeth were extracted, 7 by surgical extraction and 43 by simple extraction. Of the 17 patients included 9 of them suffering from factor VII deficiency, 5 from factor V deficiency, 1 from Glanzmann's thrombasthenia and 2 from Haemophilia A. Pretreatment with recombinant activated factor VII was performed on a total of 8 patients with factor VII deficiency; the remaining 9 patients underwent tranexamic acid treatment. 1 hemorragic postoperative complication was observed. Conclusions: Surgical and no surgical extractions appear to be a safe procedure for patients affected by coagulation disorders when appropriate prophylaxis is adopted.

This article aims to delve into the Equity, Diversity and Inclusivity (EDI) issues prevalent in the engineering disciplines in Canada and Spain, shedding light on the common obstacles faced by underrepresented individuals and highlighting potential strategies to foster a more inclusive and diverse engineering community in these nations. Two strategic lines have been identified: (a) facilitating university education access to underrepresented and minority groups, and (b) Accompanying and guiding such students during university training, setting them up for successful future careers. The article also shows the sets of strategies employed in Canada and Spain, clearly distinguishing the approach taken in the two countries. While in Canada, there is a more decentralized approach wherein the universities device their strategies and agenda to address EDI issues, in Spain there is a stronger and direct involvement of the government to ensure a comprehensive, system-wide approach to tackling EDI issues in academia.

Forty-five male Dorper crossbred lambs (40.17 ± 0.35 kg BW) were used in order to investigate the effects of the duration of calcium propionate (CaPr) supplementation in lambs finished with zilpaterol hydrochloride (ZH) on the productive performance, carcass characteristics, and meat quality. Lambs were individually housed and fed a finishing-diet for 42 d before being slaughtered. Lambs received the following treatments: 1) No additives (CTL), 2) ZH supplementation for 28 d (with 3 d ZH withdrawal before slaughter) at a dosage of at 7.2 mg/kg diet (ZH), for treatments 3, 4, and 5, lambs received ZH and 10g CaPr/lamb/d throughout the entire phase (42 d), or during the last 28 or 14 d before slaughter. Compared to CTL, ZH lambs exhibited a similar average daily gain (ADG) but had lower dry matter intake (DMI), leading to increased feed efficiency. Supplementing with ZH alone did not affect carcass traits, visceral mass, whole cuts, or meat quality. Lambs that received both CaPr and ZH exhibited quadratic increases (p < 0.05) in final BW (FBW), ADG, and dressing percentage (D%). These increases were optimal at an estimated inclusion durations of 26 d for FBW, 30 for ADG, and 39 d for D%. The ADG:DMI ratio and the longissimus muscle area (LMA) both exhibited quadratic increases (p < 0.05). The optimal duration of CaPr supplementation for ADG:DMI ratio was found to be 28 d, while for LMA, it was 14 d. As the period of CaPr supplementation increased, there was a linear increase (p <0.05) in hot carcass weight, leg circumference, and whole cuts of breast IMPS209 and shoulder IMPS207. Cook loss percent increased quadratically (p < 0.05), being higher when CaPr was included for an estimated duration of 26 d. As the duration of CaPr supplementation increased, the purge loss percentage (PLR) also increased linearly (p < 0.05). In conclusion, including CaPr in the diet for a duration of 28 d in lambs improved the response to ZH supplementation on the productive performance, carcass weight and some whole cuts. However, it can also have a negative effect on PRL%.

Meniere Disease (MD) is a multifactorial disorder of the inner ear characterized by vertigo attacks associated with sensorineural hearing loss and tinnitus with a significant heritability. Although MD has been associated with several genes, no epigenetic studies have been performed in MD. Here we performed whole genome bisulfite sequencing in 14 MD patients and 6 healthy controls, with the aim of identifying a MD methylation signature and potential disease mechanisms. We observed a high number of differentially methylated CpGs (DMC) when comparing MD patients to controls (N= 9,545), several of them in hearing loss genes such as PCDH15, ADGRV1 and CDH23. Bioinformatic analyses of DMCs and cis-regulatory regions predicted phenotypes related to abnormal excitatory postsynaptic currents, abnormal NMDA-mediated receptor currents and abnormal glutamate-mediated receptor currents when comparing MD to controls. Moreover, we identified various DMCs in genes previously associated with cochleovestibular phenotypes in mice. We have also found 12 undermethylated regions (UMR) that were exclusive to MD, including 2 UMR in an inter CpG island in the PHB gene. We suggest that the DNA methylation signature allows to distinguish between MD patients and controls. The enrichment analysis confirms previous findings of a chronic inflammatory process underlying MD.

Liquid biopsy, based on the circulating tumor cells (CTCs) and cell-free nucleic acids has potential applications at multiple points throughout the natural course of cancer, from diagnosis to follow-up. The advantages of doing ctDNA assessment vs. tissue-based genomic profile are the minimal procedural risk, the possibility to serial testing in order to monitor disease-relapse and response to therapy over time and to reduce hospitalization costs during the entire process. However some critical issues related to ctDNA assays should be taken in consideration. The sensitivity of ctDNA assays depends on the assessment technique and genetic platforms used, on tumor-organ, stage, tumor heterogeneity, tumor clonality. The specificity is usually very high, whereas the concordance with tumor-based biopsy is generally low. In patients with renal cell carcinoma (RCC) qualitative analyses of ctDNA have been performed with interesting results regarding selective pressure from therapy, therapeutic resistance, exceptional treatment response to everolimus and mutations associated with aggressive behavior. Quantitative analyses showed variations of cfDNA levels at different tumor stage. Compared to CTC assay, ctDNA is more stable than cells and easier to isolate. Splice variants, information at single-cell level and functional assays along with proteomics, transcriptomics and metabolomics studies can be performed only in CTCs.