The use of gene-specific classification guidelines VS ACMG 2015: MODY case study

Maturity Onset Diabetes of the Young (MODY) is a form of diabetes characterized as a dominant monogenic disorder. It is caused by pathogenic or likely pathogenic variants in any of the 14 genes currently associated with the disease. Since 2015 our laboratory has employed the classification algorithm guidelines established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) for variant classification. However the process of variant classification under these guidelines can be intricate and time intensive. To address these limitations the Monogenic Diabetes Variant Classification Expert Panel (MDEP VCEP) has developed specialized guidelines for classifying MODY variants particularly those found in the GCK, HNF1A, and HNF4A genes. Our objective is to determine whether variants initially classified as VUS under the 2015 ACMG guidelines can achieve a definitive classification when re-evaluated using the specific criteria set forth by the MDEP guidelines. In this study we conducted a comparative analysis of two variants identified in patients from the Portuguese MODY Study: HNF1A c.599 G>A/(p.Arg200Gln) and GCK c.1268 T>A/p.(Phe423Tyr). The HNF1A variant was reclassified as Pathogenic, a decision influenced not only by the updated guidelines but also by collaborative data sharing between institutions This robust evidence included the number of affected individuals and their phenotypes, what lead to the upgrade of the variant classification. While the classification of the GCK variant remained VUS, it has not yet been curated by the MDEP group, so it is possible that a future re-evaluation with additional evidence can lead to a definitive classification. In conclusion, the implementation of disease specific guidelines has improved the precision of variant classification, as evidenced by the reclassification of at least one variant in our MODY Diabetes Study. The MDEP group continues to review and update variant classifications submitted to ClinVar sharing their findings.N/

Estudo do complexo hiperplasia quística do endométrio-piómetra na gata doméstica

Dissertação de Mestrado Integrado em Medicina VeterináriaMaioritariamente estudada em cadelas, a hiperplasia quística de endométrio (HQE) é uma alteração também bastante prevalente na espécie felina, sendo um factor predisponente para o aparecimento de piómetra. Deste modo, estas duas entidades são comumente designadas em conjunto, com o nome de complexo hiperplasia quística de endométrio-piómetra. A presente dissertação de mestrado incide sobre o estudo do complexo mencionado, na espécie felina doméstica. Neste sentido, caracterizou-se uma população de 50 gatas sujeitas a ovariohisterectomia em diferentes fases do ciclo éstrico, com base nos aspectos histopatológicos do útero e ovários, bem como na citologia vaginal, e nas concentrações séricas de progesterona. A avaliação da citologia vaginal permitiu determinar a fase do ciclo éstrico em que a gata se encontrava, embora nem sempre as alterações do tipo celular sejam tão evidentes como nas cadelas. Neste estudo, o número de animais em diestro não gestante foi de 18 (36%). Em 12 destas fêmeas (24%) é provável que tenha ocorrido ovulação não induzida pelo coito (espontânea), uma vez que são animais de casa e sem contacto com machos. Com uma incidência de 54% (27 em 50 animais), o complexo HQE-piómetra foi principalmente observado em fêmeas com idade superior a 6 anos (78%), embora tivesse sido diagnosticado em gatas mais jovens. Contrariamente ao que acontece nas cadelas, os estrogénios per si parecem ter um efeito indutor nas lesões de HQE observadas, que poderão ser agravadas sob acção da progesterona. Os estadios do complexo mais frequentemente observados foram I (n=11) - HQE sem infiltrações inflamatórias ou outras alterações -, e o III (n=10), que se caracteriza por lesões de HQE associadas a endometrite subaguda. Os estadios II (HQE com endometrite aguda) e IV (endometrite crónica com atrofia do endométrio) foram observados somente em 2 animais.ABSTRACT - Study of the cystic endometrial hyperplasia - pyometra complex in the domestic cat - Mostly studied in dogs, cystic endometrial hyperplasia (CEH) is also quite prevalent in cats. This condition is a predisposing factor for the development of pyometra. Therefore these entities are commonly referred to together as cystic endometrial hyperplasia - pyometra complex. This master’s dissertation focuses on the study of this complex in the domestic queen. With this purpose, a population of 50 queens subjected to ovariohysterectomy in various stages of the oestrous cycle was characterized, based on histopathological aspects of the uterus and ovaries, as well as in vaginal cytology, and serum concentrations of progesterone. Vaginal cytology allows the staging of the oestrous cycle phase, although not always the changes in the proportion of the cell type are as evident as in bitches. In this study the number of non-pregnant animals in diestrus was 18 (36%). In 12 of these females (24%) spontaneous ovulation (not induced by coitus) may probably happened since these animals lived indoors and with no tom cats. With an incidence of 54% (27 of 50 animals), CEH-pyometra complex was mainly observed in females aged over 6 years (78%), although it had been diagnosed in younger cats. Unlike bitches, estrogens per si seems to have an inducing effect in the observed lesions of CEH, which could be potentiated under the influence of progesterone. The stages of the complex more frequently observed were the stage I (n = 11) - CEH without inflammatory infiltrates or other changes - and stage III (n = 10), which is characterized by lesions of subacute endometritis associated with CEH. The stages II (CEH with acute endometritis) and IV (chronic endometritis with endometrial atrophy) were observed only in two animals

Mutação do Hnf1ß (Mody 5) - Estudo de uma família portuguesa

Prémio de Melhor Caso Clínic

Ancestry of the α-MRE Associated with the 3.7kb α-Thalassemia Deletion in the Portuguese Population

Abstract publicado em: Medicine (Baltimore). 2023 Mar 31; 102(13): e33154. Published online 2023 Mar 31. doi: 10.1097/MD.0000000000033154The α-major regulatory element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. It is genetically polymorphic and six haplotypes (A to F) have been identified in different populations. The D haplotype was primary described in African populations and is nearly absent in other populations. The aims of this study were to identify the α-MRE haplotype associated with the common 3.7kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and to investigate its ancestry. We searched for the -α3.7del in 111 selected Portuguese individuals by Gap-PCR. In addition, a DNA fragment containing the α-MRE was amplified by PCR and Sanger sequenced. Statistical analysis was performed using R software. Fifty individuals have the wild-type α-globin genotype (group I), 34 are heterozygous for the -α3.7del (group II) and 27 are homozygous (group III). Regarding the α-MRE, four haplotypes were found (A to D). The ancestral A haplotype is predominant in all groups. The B haplotype is the second most frequent in groups I and II, whereas in group III haplotype D is the second most prevalent. Concerning genotypes, the α-MRE AA and AB are the most common in group I, while genotype AD is more prevalent in group III. In fact, 71.4% of AD individuals are homozygous for the -α3.7del. Moreover, the distribution of α-MRE haplotypes and genotypes are significantly different between groups with and without the -α3.7del (p<0.001). Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are split from these and found to be more closely related to the African population. This study revealed for the first time an association of a specific α-MRE haplotype with the common -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as the D haplotype has an alteration in the consensus sequence for the AP-1/NF-E2 binding site and in vitro experiments showed a decrease in its enhancer activity on α-globin genes.info:eu-repo/semantics/publishedVersio

A Qualitative Evidence Synthesis Protocol

Nursing Bedside Handover (NBH) is acknowledged as a nursing practice implemented at the patient’s bedside to improve communication safety during the shift change, but it is vulnerable due to inconsistent application among nurses. This synthesis of qualitative evidence aims to review and synthesize the perceptions and experiences of nurses regarding the factors that, in their perspective, influence NBH practice. We will follow the thematic synthesis methodology of Thomas and Harden and the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) Statement guidelines. A search will be conducted through the databases of MEDLINE, CINAHL, Web of Science, and Scopus, and we will follow the three-step search process to identify primary studies with qualitative or mixed-method research designs and projects of quality improvement. The screening and selection of the studies will be carried out by two independent reviewers. We will use the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) to report the screening, search, and selection of studies. To assess its methodological quality, two reviewers will independently use the CASM Tool. The extracted data will be reviewed, categorized, and summarized in tabular and narrative formats. The findings obtained will allow us to inform future research and change management led by nurse managers.info:eu-repo/semantics/publishedVersio