Applying WHO2013 diagnostic criteria for gestational diabetes mellitus reveals currently untreated women at increased risk.

AIMS: To estimate the prevalence of gestational diabetes mellitus (GDM) in a Danish cohort comparing the current Danish versus the WHO2013 diagnostic criteria, and to evaluate adverse pregnancy outcomes among currently untreated women in the gap between the diagnostic thresholds. METHODS: Diagnostic testing was performed by a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks' gestation in a cohort of pregnant women. GDM diagnosis was based on the current Danish criterion (2-h glucose ≥ 9.0 mmol/L, GDMDK) and on the WHO2013 criteria (fasting ≥ 5.1, 1 h ≥ 10.0 or 2 h glucose ≥ 8.5 mmol/L, GDMWHO2013). Currently untreated women fulfilling the WHO2013 but not the Danish diagnostic criteria were defined as New-GDM-women (GDMWHO2013-positive and GDMDK-negative). Adverse outcomes risks were calculated using logistic regression. RESULTS: OGTT was completed by 465 women at a median of 25.7 weeks' gestation. GDMDK prevalence was 2.2% (N = 10) and GDMWHO2013 21.5% (N = 100). New-GDM was present in 19.4% (N = 90), of whom 90.0% had elevated fasting glucose. Pregnancies complicated by New-GDM had higher frequencies of pregnancy-induced hypertension (13.3% vs 4.1%, p = 0.002), large-for-gestational-age infants (22.2% vs 9.9%, p = 0.004), neonatal hypoglycaemia (8.9% vs 1.9%, p = 0.004) and neonatal intensive care unit admission (16.7% vs 5.8%, p = 0.002) compared to pregnancies without GDM. CONCLUSIONS: GDM prevalence increased tenfold when applying WHO2013 criteria in a Danish population, mainly driven by higher fasting glucose levels. Untreated GDM in the gap between the current Danish and the WHO2013 diagnostic criteria resulted in higher risks of adverse pregnancy outcomes.

Association of COVID-19 and Development of Type 1 Diabetes: A Danish Nationwide Register Study.

OBJECTIVE: To compare the incidence of type 1 diabetes (T1D) before and during the coronavirus disease 2019 (COVID-19) pandemic and determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with T1D development. RESEARCH DESIGN AND METHODS: All Danish residents aged <30 years free of diabetes from 2015 to 2021 were included. Individuals were followed from 1 January 2015 or birth until the development of T1D, the age of 30, the end of the study (31 December 2021), emigration, development of type 2 diabetes, onset of any cancer, initiation of immunomodulating therapy, or development of any autoimmune disease. We compared the incidence rate ratio (IRR) of T1D using Poisson regression models. We matched each person with a SARS-CoV-2 infection with three control individuals and used a cause-specific Cox regression model to estimate the hazard ratio (HR). RESULTS: Among 2,381,348 individuals, 3,579 cases of T1D occurred. The adjusted IRRs for T1D in each quarter of 2020 and 2021 compared with 2015-2019 were as follows: January-March 2020, 1.03 (95% CI 0.86; 1.23); January-March 2021, 1.01 (0.84; 1.22), April-June 2020, 0.98 (0.80; 1.20); April-June 2021, 1.34 (1.12; 1.61); July-September 2020, 1.13 (0.94; 1.35); July-September 2021, 1.21 (1.01; 1.45); October-December 2020, 1.09 (0.91; 1.31); and October-December 2021, 1.18 (0.99; 1.41). We identified 338,670 individuals with a positive SARS-CoV-2 test result and matched them with 1,004,688 control individuals. A SARS-2-CoV infection was not significantly associated with the risk of T1D development (HR 0.90 [95% CI 0.60; 1.35]). CONCLUSIONS: There was an increase in T1D incidence during April-June 2021 compared with April-June 2015-2019, but this could not be attributed to SARS-CoV-2 infection.

Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report.

BACKGROUND: Thyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. Early diagnosis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias. CASE PRESENTATION: A 19-year-old Caucasian man was admitted acutely with paralysis in upper and lower limbs and tachycardia. Over several months, he had experienced anxiousness, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools, and had lost 21 kg over the last year. Initial blood gas showed very low potassium of 1.4 mM, and blood tests showed decreased Thyroid-stimulating hormone (TSH) < 0.01 × 10- 3 IU/L, elevated free thyroxine (fT4) of 63.5 pM (reference interval (RI): 12.0-22.0 pM), and elevated total triiodothyronine (T3) of 8.2 nM (RI: 1.0-2.6 nM). He was diagnosed with TPP and treated with liquid oral potassium chloride (30 mmol every 30 minutes) and propylthiouracil (initial dose of 400 mg followed by 200 mg three times daily). TSH-receptor antibodies (TRAB) and thyroid-peroxidase antibodies (TPO-ab) were highly elevated. Thyroid ultrasound showed a normal-sized gland and color Doppler sonography showed increased vascularity throughout the gland, compatible with Graves' disease. He was discharged on day 4 with a normal potassium level and followed in the outpatient clinic where he received standard care for Graves' disease. Genetic testing using whole-genome sequencing found no genetic variants in genes previously associated with TPP. CONCLUSION: TPP is very rare in Caucasians but more often affects young men in East Asian populations. The case presents a Caucasian man with TPP where genetic testing of CACNA1S, KCNJ18, SCN4A, KCNJ2, KCNE3, and ABCC8 shows no pathogenic variants in genes previously associated with TPP.

Risk factors for fatigue and impaired function eight months after hospital admission with COVID-19.

INTRODUCTION: We aimed to evaluate post-COVID-19 fatigue, change in functional capacity and health-related quality of life (HRQoL) eight months after discharge from hospital due to COVID-19. METHODS: A total of 83 patients (35 women) admitted to the Copenhagen University Hospital - North Zealand Hospital, Denmark, for COVID-19 during the period from March to June 2020 were evaluated eight months after discharge using validated questionnaires quantifying fatigue, HRQoL and post-COVID-19 functional status. Follow-up data were correlated with measures of pre-COVID-19 status (anthropometrics, comorbidities) and measures of severity of the acute infection. RESULTS: A total of 22 (65%) women and 12 (26%) men reported excessive fatigue. In all, 20 women (67%) and 17 men (37%) reported decreased physical function. Female sex was associated with fatigue. Loss of physical function was associated with pre-COVID-19 presence of heart disease and absence of lung disease. Severity of the acute COVID-19 infection was not associated with fatigue or change in functional status. Fatigue and functional status were correlated with both generic HRQoL and lung disease-specific HRQoL. CONCLUSIONS: Female sex was associated with a higher risk of fatigue eight months after hospitalisation with COVID-19 infection. Regarding loss of functional capacity after COVID-19, we found an apparently protective effect of pre-COVID-19 lung disease. Our findings underscore the urgent need for further research and the importance of evaluating those recovering from COVID-19 for symptoms of excessive fatigue and change in functional capacity irrespective of the severity of the initial infection. FUNDING: none. TRIAL REGISTRATION: not relevant.

Metabolic Syndrome in Male Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Total Body Irradiation, Low-Grade Inflammation, and Hypogonadism.

Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. This study aimed to determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and to investigate predisposing factors, including low-grade inflammation, altered fat distribution, and low testosterone levels. We included 98 survivors age 19 to 47 years at a median follow-up of 18 years (range, 8 to 35 years) after pediatric HSCT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence and clinical manifestations of MetS were compared between our cohort and a control group of males from the background population (n = 4767). Fat distribution was assessed by android/gynoid ratio from a whole-body dual-energy X-ray absorptiometry scan. Systemic inflammation was evaluated by IL-6 and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. The prevalence of MetS was 30%, corresponding to the prevalence in the 50- to 80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared with age-matched controls with MetS (76% versus 20%; P < .001), whereas hypertension was more dominant in the control group with MetS (69% versus 93%; P = .01). In addition, normal or low body mass index was more commonly observed among HSCT survivors with MetS compared with age-matched controls with MetS (41% versus 11%; P = .002). MetS was more often associated with total body irradiation (TBI) compared with chemotherapy regimens (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2 to 24.4; P = .02), lower testosterone levels (OR, 5.4; 95% CI, 1.3 to 23.6; P = .02), higher IL-6 levels (OR, 1.8; 95% CI, 1.2 to 2.8; P = .004), and higher hsCRP levels (OR, 1.8; 95% CI, 1.3 to 2.6; P < .001) (estimates per 2-fold increase). In addition, an increased android/gynoid (AG) fat ratio was strongly associated with MetS (OR, 2.1; 95% CI, 1.5 to 2.9; P < .001), even though only 7% of patients met the criteria for increased abdominal circumference. Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestations differed from those seen in age-matched controls with MetS, indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardiometabolic risk profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared with the background population.

Characteristics and early outcomes of patients hospitalised for COVID-19 in North Zealand, Denmark.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an ongoing pandemic associated with significant morbidity and mortality worldwide. Limited data are available describing the clinical presentation and outcomes of hospitalised COVID-19 patients in Europe. METHODS: This was a single-centre retrospective chart review of all patients with COVID-19 admitted to the North Zealand Hospital in Denmark between 1 March and 4 May 2020. Main outcomes include major therapeutic interventions during hospitalisation, such as invasive mechanical ventilation, as well as death. RESULTS: A total of 115 patients were included, including four infants. The median age of adults was 68 years and 40% were female. At admission, 55 (50%) patients had a fever, 29 (26%) had a respiratory rate exceeding 24 breaths/minute, and 78 (70%) received supplemental oxygen. The prevalence of co-infection was 13%. Twenty patients (18%) (median age: 64 years; 15% female) were treated in the intensive care unit. Twelve (10.4%) received invasive mechanical ventilation and three (2.6%) renal replacement therapy. Nine patients (8%) developed pulmonary embolism. Sixteen patients (14%) died. Among patients requiring mechanical ventilation (n = 12), seven (6.1%) were discharged alive, four (3.4%) died and one (0.9%) was still hospitalised. CONCLUSION: In this cohort of hospitalised COVID-19 patients, mortality was lower than in other Danish and European case series. FUNDING: none. TRIAL REGISTRATION: not relevant.

Selenium supplementation for patients with Graves' hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial.

BACKGROUND: Graves' hyperthyroidism is an autoimmune disease causing hyperfunction of the thyroid gland. The concentration of selenium is high in the thyroid gland and two important groups of enzymes within the thyroid are selenoproteins, that is, they depend on selenium. Selenium may have beneficial effects on autoimmune hypothyroidism and on Graves' orbitopathy, but the effects of selenium on Graves' hyperthyroidism is unknown.We hypothesize that adjuvant selenium may be beneficial in the treatment of Graves' hyperthyroidism. The objective is to investigate if selenium supplementation plus standard treatment with anti-thyroid drugs versus standard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid drug treatment failure (that is, failure to remain euthyroid, without further treatment, one year after cessation of anti-thyroid drug treatment), faster and longer lasting remission (that is, anti-thyroid drug treatment success), and improved quality of life in patients with Graves' hyperthyroidism. METHODS AND DESIGN: The trial is an investigator-initiated, randomised, blinded, multicentre clinical trial. Inclusion criteria are: age 18 years or older; diagnosis of active Graves' hyperthyroidism within the last two months; and informed consent. Exclusion criteria are major co-morbidity; previous radioactive iodine treatment; ongoing anti-thyroid drug treatment for more than two months; treatment with immunomodulatory drugs; known allergy towards the components in the selenium and placebo pills; pregnancy or breast-feeding; and intake of selenium supplementation above 70 µg per day. We plan to include 492 participants, randomised (1:1) to two tablets of 100 µg selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily.The primary outcome is the proportion of participants with anti-thyroid drug treatment failure (see above) at the end of the intervention period (24 to 30 months). Secondary outcomes are: thyroid-specific quality of life during the first year after randomisation; level of thyroid stimulating hormone-receptor antibodies at 18 months after randomisation and at the end of the intervention period (24 to 30 months); hyperthyroid symptoms during the first year after randomisation; eye symptoms during the first year after randomisation, and at the end of the intervention period (24 to 30 months); adverse reactions during the intervention period; and serious adverse events during the intervention period. DISCUSSION: It was of great importance to the initiators of this trial, that the results would be directly applicable to daily clinical practice. Therefore, it was designed as a pragmatic trial: the patients follow their usual treatment at their usual hospitals. In order to still collect high quality data on the clinical course and quality of life, an elaborate trial management system was designed to keep track of patient input, need for trial personnel input and action, and to collect data from medical chart systems. Meticulous follow-up on missing responses to the QoL measurements has been incorporated into the system, to minimise missing quality of life data. Monitoring of adverse reactions and events is achieved by thorough instruction of the participants, surveillance of patient-reported outcomes, and integration with national databases regarding hospitalizations. A very long intervention period was necessary, since patients are not considered in remission until one year after stopping anti-thyroid drugs. Usually, patients are treated for 12 to 18 months with anti-thyroid drugs, yielding a total intervention period of 24 to 30 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01611896.

Is puberty an accelerator of type 1 diabetes in IL6-174CC females?

The pubertal peak in onset of type 1 diabetes occurs earlier in girls than boys. We postulated that this sex difference might be mediated in part by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene. Previous studies concerning the role of an estrogen-sensitive single nucleotide polymorphism (SNP) in the IL6 promoter in type 1 diabetes have proved contradictory. We therefore selected a large, genetically homogenous population-based cohort, analyzed by age at onset and sex, to test the hypothesis that the IL6-174G>C SNP affects age at onset of type 1 diabetes in females but not in males. We found that the IL6-174CC genotype was significantly less frequent in females diagnosed after than in those diagnosed before the age of 10 years (19 vs. 13%, P = 0.016). No genotype difference was observed in males stratified for age at onset. Among children diagnosed after age 10, the median age of onset was 11.9 years (intraquartile range 10.7-14.6) in 34 girls homozygous for IL6-174C compared with 13.2 years (11.6-15.4) in 229 girls with other genotypes and 13.5 years (12.0-15.6) in 339 males with any IL6-174 genotype (P = 0.012). These data support the hypothesis that pubertal changes may contribute to accelerated onset of type 1 diabetes in genetically susceptible females. This phenomenon may be orchestrated by the action of estrogen on the IL6 promoter.

Mutation scan of a type 1 diabetes candidate gene: the human interleukin-18 binding protein gene.

Type 1 (insulin-dependent) diabetes, T1DM, is the result of an immune-mediated destruction of the pancreatic beta cells dependent mainly on T helper cells and macrophages. Interleukin-18 (IL-18) is a proinflammatory cytokine produced mainly by macrophages. IL-18 is capable of inducing T lymphocyte synthesis of IFNgamma, thereby skewing the T helper response toward a T helper type 1 (Th1) profile. IL-18 binding protein (IL18BP) neutralizes IL-18 and leads to a reduced Th1 response. Polymorphisms in IL18BP may affect the activity of IL-18 and the magnitude of the Th1 response and may play a role in the pathogenesis of T1DM. The aim of the study was therefore to identify polymorphisms in IL18BP and to test these for association with T1DM. We evaluated the human IL18BP gene on chromosome 11q13 as a candidate susceptibility gene for T1DM and scanned the entire IL18BP (promoter, exons 1-6, and 3'UTR) for polymorphisms using single-strand conformational polymorphism analysis and direct sequencing. We identified a total of 11 polymorphisms, all having allele frequencies ranging between 0.05 and 0.10. Four were in the 5'UTR: -257G-->T, -78C-->T, -65G-->A, and -59A-->G. Three were in intron 3: IVS3+140A-->C, IVS4-147G-->T, and IVS4-59G-->T. The last four, 38*A-->T, 48*T-->A, 388*C-->G, and 440*_441*insG, were in the 3'UTR of IL18BP. However, none of these were frequent enough to permit association studies in T1DM and we conclude that IL18BP does not contribute to the overall genetic susceptibility to type 1 diabetes.

Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females.

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, P(tdt)=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; P(tdt)=6.5 x 10(-4) and P(tdt)=2.4 x 10(-4), respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all P(tdt)>/=0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-estradiol (E(2)) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by approximately 70% in the absence of E(2) (P(c)=0.004), but not with E(2) present (P(c)=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E(2) present, but was derepressed by addition of E(2), P(c)=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E(2) as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E(2) levels in puberty.