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- The Rare DRB1*04:08-DQ8 Haplotype is the Main HLA Class II Genetic Driver and Discriminative Factor of Early-Onset Type 1 Diabetes in the Portuguese PopulationPublication . Caramalho, Iris; Matoso, Paula; Ligeiro, Dário; Paixão, Tiago; Sobral, Daniel; Fitas, Ana Laura; Limbert, Catarina; Demengeot, Jocelyne; Penha-Gonçalves, CarlosIntroduction: Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control. Methods: We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in DRB1, DQA1 and DQB1 genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population. Results: Allelic association analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed that the rare DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0x10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4x10-2). In corroboration, HLA class II haplotype analysis showed that the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4x10-5) and represents the major HLA class II genetic driver and discriminative factor in the development of early onset disease. Discussion: This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility loci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings encompassing other ethnicities and may impact target screening strategies and follow-up of young children with high T1D genetic risk as well as personalized therapeutic approaches.
- Exploring Early DNA Methylation Alterations in Type 1 Diabetes: Implications of Glycemic ControlPublication . Čugalj Kern, Barbara; Kovač, Jernej; Šket, Robert; Tesovnik, Tine; Jenko Bizjan, Barbara; Galhardo, Julia; Battelino, Tadej; Bratina, Nataša; Dovč, KlemenBackground: Prolonged hyperglycemia causes diabetes-related micro- and macrovascular complications, which combined represent a significant burden for individuals living with diabetes. The growing scope of evidence indicates that hyperglycemia affects the development of vascular complications through DNA methylation. Methods: A genome-wide differential DNA methylation analysis was performed on pooled peripheral blood DNA samples from individuals with type 1 diabetes (T1D) with direct DNA sequencing. Strict selection criteria were used to ensure two age- and sex-matched groups with no clinical signs of chronic complications according to persistent mean glycated hemoglobin (HbA1c) values over 5 years: HbA1c<7% (N=10) and HbA1c>8% (N=10). Results: Between the two groups, 8385 differentially methylated CpG sites, annotated to 1802 genes, were identified. Genes annotated to hypomethylated CpG sites were enriched in 48 signaling pathways. Further analysis of key CpG sites revealed four specific regions, two of which were hypermethylated and two hypomethylated, associated with long non-coding RNA and processed pseudogenes. Conclusions: Prolonged hyperglycemia in individuals with T1D, who have no clinical manifestation of diabetes-related complications, is associated with multiple differentially methylated CpG sites in crucial genes and pathways known to be linked to chronic complications in T1D.
- The Use of Continuous Glucose Monitoring in People Living with Obesity, Intermediate Hyperglycemia or Type 2 Diabetes.Publication . Battelino, Tadej; Lalic, Nebojsa; Hussain, Sufyan; Ceriello, Antonio; Klobucar, Sanja; Davies, Sarah J; Topsever, Pinar; Heverly, Julie; Ulivi, Francesca; Brady, Kevin; Tankova, Tsvetalana; Galhardo, Júlia; Tagkalos, Kostas; Werson, Erik; Mathieu, Chantal; Schwarz, PeterA global trend towards increased obesity, intermediate hyperglycemia (previously termed prediabetes) and type 2 diabetes, has prompted a range of international initiatives to proactively raise awareness and provide action-driven recommendations to prevent and manage these linked disease states. One approach, that has shown success in managing people already diagnosed with type 2 diabetes mellitus, is to use continuous glucose monitoring (CGM) devices to help them manage their chronic condition through understanding and treating their daily glucose fluctuations, in assocation with glucose-lowering medications, including insulin. However, much of the burden of type 2 diabetes mellitus is founded in the delayed detection both of type 2 diabetes mellitus itself, and the intermediate hyperglycemia that precedes it. In this review, we provide evidence that using CGM technology in people at-risk of intermediate hyperglycemia or type 2 diabetes mellitus can significantly improve the rate and timing of detection of dysglycemia. Earlier detection allows intervention, including through continued use of CGM to guide changes to diet and lifestyle, that can delay or prevent harmful progression of early dysglycemia. Although further research is needed to fully understand the cost-effectiveness of this intervention in people at-risk or with early dysglycemia, the proposition for use of CGM technology is clear.
- Association Between COVID-19 and the Incidence of Type 1 Diabetes in Portugal - a Registry StudyPublication . Bjerregaard-Andersen, Morten; Da Silva, Jessica; Diogo, Rui; Claro, Ana Raquel; Ferro, Inês; Romana, Andreia; Rocha, Patrícia; Sá, Beatriz; Lobarinhas, Goreti; Rolim, Sara; Juhl, Claus Bogh; Højlund, Kurt; Fernandes, Isabel; Antunes, Sónia; Félix Calha, Maria Manuela; Gama, Guida; Amálio, Sofia; Figueiras, Mariana; Silva, Teresa; Rosado, Margarida; Ferrão, Estela; Arez, Luísa; Baptista, Ana; Martins Ferreira, Adriana; Alba, Diana; Godinho, Carlos; Leite, Ana Luísa; Lopes, Lurdes; Sampaio, Maria Lurdes; Serra-Caetano, Joana; Carvalho, EugeniaBackground: Viral respiratory infections may precipitate type 1 diabetes (T1D). A possible association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, and the incidence of T1D is being determined. This study was carried out using Portuguese registries, aiming at examining temporal trends between COVID-19 and T1D. Methods: Hospital data, comparing the incidence before and during the COVID-19 pandemic, from children and young adults diagnosed with new-onset T1D, was acquired beginning in 2017 and until the end of 2022. Data was obtained from nine different Portuguese hospital units. The impact of the COVID-19 pandemic, beginning in March 2020, was assessed comparing the annual numbers of new-onset T1D cases. The annual median levels of glucose, glycated hemoglobin (HbA1c) and fasting C-peptide at T1D diagnosis were compared. The annual number of diabetic ketoacidosis (DKA) episodes among new T1D cases was also assessed at two centers. Results: In total, data from 574 newly diagnosed T1D patients was analyzed, including 530 (92.3%) children. The mean ages for child and adult patients were 9.1 (SD 4.4) and 32.8 (SD 13.6) years, respectively. 57.8% (331/573) were male, one patient had unknown sex. The overall median (25-75 percentiles) levels of glucose, HbA1c and fasting C-peptide at diagnosis were 454 mg/dL (356-568), 11.8% (10.1-13.4) and 0.50 µg/L (0.30-0.79), respectively. DKA at T1D diagnosis was present in 48.4% (76/157). For eight centers with complete 2018 to 2021 data (all calendar months), no overall significant increase in T1D cases was observed during the COVID-19 pandemic, i.e. 90 cases in 2018, 90 cases in 2019, 112 in 2020 and 100 in 2021 (P for trend = 0.36). Two of the centers, Faro (CHUA) and Dona Estefânia (CHULC) hospitals, did however see an increase in T1D from 2019 to 2020. No significant changes in glucose (P = 0.32), HbA1c (P = 0.68), fasting C-peptide (P = 0.20) or DKA frequency (P = 0.68) at the time of T1D diagnosis were observed over the entire study period. Conclusion: The T1D incidence did not increase significantly, when comparing the years before and during the COVID-19 pandemic, nor did key metabolic parameters or number of DKA episodes change.
- Personalizing Early-Stage Type 1 Diabetes in ChildrenPublication . Limbert, C; von dem Berge, T; Danne, T
- Height Benefit of GnRH Agonists After Age 8 in a Portuguese Cohort of Central Precocious PubertyPublication . Castro, C; Espada, F; Leite, AL; Antunes, A; Robalo, B; Amaral, D; Galo, E; Castro, S; Ferreira, S; Limbert, CObjective: Idiopathic central precocious puberty (iCPP) is common in paediatric endocrinology. Gonadotropin-releasing hormone agonists (GnRHa) are safe, but the effect on final height and the ideal timing for treatment remains controversial. This study aims to assess the effectiveness of GnRHa on growth outcomes in girls with iCPP treated before and after the age of 8 years old. Design and patients: This retrospective longitudinal study evaluated data from Portuguese girls with iCPP who completed treatment between 2010 and 2021. Measurements: Auxological and clinical characteristics were compared according to age at treatment onset. Results: A cohort of 134 girls with iCPP, was divided into early treatment (ET) (<8 years, n = 48) and later treatment (LT) groups (≥8 years, n = 86). In both groups, most children presented with Tanner II and III. Tanner IV was more frequent in LT group (p = .003). At the end of treatment, predicted adult height increased in both groups (ET p = .032; LT p = .04) and bone age significantly slowed down in all participants (p = .008, p = .034). The height gain was greater in the ET group, but without significant differences (p = .065). Conclusions: Treatment with GnRHa improved final height in all girls with iCPP, even when initiated after 8 years. To achieve better outcomes, treatment should be provided promptly after diagnosis
- The COVID-19 Pandemic Affects Seasonality, With Increasing Cases of New-Onset Type 1 Diabetes in Children, From the Worldwide SWEET RegistryPublication . Reschke, F; Lanzinger, S; Herczeg, V; Prahalad, P; Schiaffini, R; Mul, D; Clapin, H; Zabeen, B; Pelicand, J; Phillip, M; Limbert, C; Danne, T; Alonso, GT; Rhodes, ET; Davis, E; Veeze, HJ; Maahs, D; Cardona-Hernandez, R; Sumnik, Z; Corathers, S; Bratina, N; Danne, T; Gevers, E; Imane, Z; Piccini, B; Forsander, G; Pacaud, D; Maffeis, C; Campbell, F; Bonfanti, R; de Sanctis, L; Krone, RE; Toth-Heyn, P; Witsch, M; Arsanoglu, I; Jefferies, C; Landry, A; Beltrand, J; Amed, S; Rami-Merhar, B; Barat, P; Szypowska, A; Zabeen, B; Casteels, K; Savova, R; Cherubini, V; de Bock, M; Todorovic, S; Limbert, C; Moravej, H; Pozgaj Sepac, M; Mazur, A; Gerasimidou-Vazeou, A; Iotova, V; O’Riordan, S; Chobot, A; Herbst, A; Ngwu, U; Cody, D; Birkebæk, NH; Hanas, R; Goksen, D; Sarda, A; Chobot, J; Mirante, A; Richmond Padilla, E; Tsiroukidou, K; Saboo, B; Kanaka-Gantenbein, C; Schiaffini, R; Foskett, D; Jali, S; Verkauskiene, R; Castro-Correia, C; Kumar Guness, P; Pelicand, J; Cotterill, A; Kumari Mohan, M; Spehar Uroic, A; Goss, P; Svensson, J; Ramchandani, GD; Coutant, R; Mantilla, L; Sima, A; Hyun Kim, J; Galli-Tsinopoulou, A; Ribeiro, R; O’Gorman, C; Fonna, H; Bratke, H; El Habashy, S; Gokalani, R; Scharf Pinto, M; Chavda, VObjective: To analyze whether the coronavirus disease 2019 (COVID-19) pandemic increased the number of cases or impacted seasonality of new-onset type 1 diabetes (T1D) in large pediatric diabetes centers globally. Research design and methods: We analyzed data on 17,280 cases of T1D diagnosed during 2018-2021 from 92 worldwide centers participating in the SWEET registry using hierarchic linear regression models. Results: The average number of new-onset T1D cases per center adjusted for the total number of patients treated at the center per year and stratified by age-groups increased from 11.2 (95% CI 10.1-12.2) in 2018 to 21.7 (20.6-22.8) in 2021 for the youngest age-group, <6 years; from 13.1 (12.2-14.0) in 2018 to 26.7 (25.7-27.7) in 2021 for children ages 6 to <12 years; and from 12.2 (11.5-12.9) to 24.7 (24.0-25.5) for adolescents ages 12-18 years (all P < 0.001). These increases remained within the expected increase with the 95% CI of the regression line. However, in Europe and North America following the lockdown early in 2020, the typical seasonality of more cases during winter season was delayed, with a peak during the summer and autumn months. While the seasonal pattern in Europe returned to prepandemic times in 2021, this was not the case in North America. Compared with 2018-2019 (HbA1c 7.7%), higher average HbA1c levels (2020, 8.1%; 2021, 8.6%; P < 0.001) were present within the first year of T1D during the pandemic. Conclusions: The slope of the rise in pediatric new-onset T1D in SWEET centers remained unchanged during the COVID-19 pandemic, but a change in the seasonality at onset became apparent.
- Case Report: Fourth Branchial Cleft Cyst: A Case of Acute Suppurative ThyroiditisPublication . Caseiro Alves, ME; Nunes, A; Galhardo, JThis case report presents a 4 year-old-female patient with a neck mass who was diagnosed with an infected fourth branchial cleft cyst with left thyroid lobe involvement through fistulation. The case emphasizes the importance of considering uncommon etiologies, such as congenital anomalies, as a differential diagnosis when evaluating pediatric neck masses. The patient was prescribed broad-spectrum antibiotics, which led to the regression of the mass and inflammatory signs. Close follow-up in endocrinology and otorhinolaryngology appointments was maintained, and after 7 months, hypoplasia of the left lobe was observed. Thyroid function was reevaluated, and after two years, no recurrences were noted. The case highlights the significance of a comprehensive examination and assessment of corresponding clinical features, which can significantly reduce the rate of misdiagnoses and achieve an individualized diagnosis.
- Preoperative Location of Parathyroid Adenomas in Primary Hyperparathyroidism: the Role of Cervical Doppler UltrasoundPublication . Amaral, S; Rego, T; Palha, A; Carrilho, N; Coutinho, JM; Tavares, P; Silva-Nunes, JIntroduction: Parathyroid adenoma is the most frequent cause of primary hyperparathyroidism. In recent years, the preoperative location of parathyroid adenomas allowed minimally invasive surgical techniques that have become preferred over the traditional bilateral neck exploration. The more recent guidelines on this subject highlight the role of nuclear medicine imaging tests. The aim of this study was to review the current role of Doppler ultrasound (US) in assessing the preoperative location of parathyroid adenomas in patients with primary hyperparathyroidism. Material and methods: Retrospective study based on data from patients with primary hyperparathyroidism that underwent parathyroidectomy between January 2013 and January 2022 at the Centro Hospitalar Universitário Lisboa Central. Statistical analysis was performed with IBM SPSS Statistics, version 26.0.0.0®. Results: Parathyroidectomy was performed in 171 patients (77.8% females) with primary hyperparathyroidism. Cervical Doppler ultrasound was the most performed test (64.3%, n = 110) for preoperative location and detected a suspicious lesion in 98 patients (89.1%). The preoperative location of the parathyroid adenomas was assessed through the Doppler ultrasound and was compared with the surgical reports and histological findings; a correct identification was made in 76 patients (77.6%). Doppler ultrasound slightly underestimated the mean adenoma size (18.1 ± 7.7 mm preoperative versus 22 ± 8.4 mm postoperative). Calcium, parathyroid hormone levels, adenoma size and concomitant presence of thyroid nodules did not affect the accuracy of Doppler ultrasound. Conclusion: Doppler ultrasound showed high diagnostic accuracy even in patients with nodular thyroid disease regardless of calcium and parathyroid hormone levels and adenoma size. Furthermore, its safety, affordability and availability should favor its use as first line test in primary hyperparathyroidism to assess the preoperative location of parathyroid adenomas.
- ISPAD Clinical Practice Consensus Guidelines 2022: The delivery of ambulatory diabetes care to children and adolescents with diabetesPublication . Limbert, C; Tinti, D; Malik, F; Kosteria, I; Messer, L; Jalaludin, YM; Benitez‐Aguirre, P; Biester, S; Corathers, S; von Sengbusch, S; Marcovecchio, ML