To Örebro University

BACKGROUND AND AIMS: Patients with childhood-onset type 1 diabetes (T1D) are at increased risk of developing microvascular complications, including neuropathy and nephropathy. Hormonal dysregulation and markers of atherosclerotic plaque instability and platelet activation may play key roles in the pathogenesis of these complications. The aim of this study was to investigate the impact of hormonal levels on atherosclerotic risk markers and platelet function, as well as to explore the association between diabetic neuropathy and nephropathy in individuals with childhood-onset type 1 diabetes.

METHODS: In this cross-sectional analysis of a longitudinal cohort, 34 individuals with childhood-onset type 1 diabetes (mean age 27.6 ± 4.2 years; diabetes duration 8.2 ± 5.6 years) were examined. S-IGF-I, long-term HbA1c, micro/macroalbuminuria, triiodothyronine and thyroxine, S-Cortisol, P-ACTH, P-Renin, sP-Selectin, P-MMP-9, P-TIMP-1, P-Adiponectin, and platelet adhesion to albumin, collagen, and fibrinogen were assessed. An abnormality in nerve conduction tests was defined as diabetic neuropathy.

RESULTS: S-IGF-I was negatively correlated with age (r = -0.36, p = 0.007), and with long-term HbA1c (r = -0.426, p = 0.019, corrected for age). IGF-I levels in patients diagnosed with clinical neuropathy (n = 6) were lower (123 ± 38 µg/L) than in patients without neuropathy (n = 26, 178 ± 56 µg/L, p = 0.029). S-IGF-I levels were also lower in patients with nephropathy (n = 7, 122 ± 28 µg/L) compared with patients without nephropathy (n = 27, 180 ± 60 µg/L, p = 0.02). S-IGF-I was negatively correlated with P-TIMP-1 (r = -0.44, p = 0.009), sP-Selectin (r = -0.53, p = 0.001), and positively correlated with platelet adhesion to fibrinogen (r = 0.38, p = 0.035). S-free-Triiodothyronine correlated negatively with P-MMP-9, (r = -0.46, p = 0.005), and P-MMP-/P-TIMP-1 ratio (r = -0.40, p = 0.018), and P-Adiponectin (r = -0.49, p = 0.018). P-Renin correlated negatively with P-Adiponectin (r = -0.34, p = 0.045).

CONCLUSIONS: Low serum IGF-I levels were associated with the presence of diabetic neuropathy and nephropathy in young adults with type 1 diabetes. Additionally, both IGF-I and S-free-Triiodothyronine levels were linked to changes in platelet activation and atherosclerotic markers, suggesting that hormonal dysregulation may contribute to early vascular complications in this population.

BACKGROUND: Turner syndrome (TS) is a complex genetic disorder with raised mortality. Our objective was to investigate mortality and causes of death in TS.

METHODS: A matched retrospective observational study of women with TS recruited from the Turner centers in Sweden were conducted. A total of 472 women with TS, ≥ 16 years old with a cytogenetically verified diagnosis and 2357 controls, matched for birthyear and sex, were examined and followed since 1995 for up to 26 years. Survival analyses were performed with Cox proportional hazard models. Kaplan-Meier curves were generated. Cumulative incidence rates were evaluated by competing risks analysis, using cumulative incidence function.

RESULTS: During a mean follow-up of 17 years, 35 (7.4%) women with TS and 70 (3.0%) controls died. All-cause mortality was elevated in TS, hazard ratio (HR) 2.90 (95% CI 1.92-4.37), mainly due to circulatory diseases and notably aortic dissection, with HR of 9.11 (95% CI 4.54-18.25) and 21.79 (95% CI 4.62-102.82), respectively. Aortic dissection was the single largest cause of death in TS, accounting for 23% (8/35) of total deaths. Death by cancer or external causes were not raised in TS. In individuals below 45 years of age death, aortic dissections were greatly increased compared to controls, HR 55.59 (95% CI 2.33-1325.69). From the ages 46 to 80 years a notably higher risk of dying by heart diseases, aortic dissection excluded, was shown in TS compared to controls HR, 7.7 (2.65-22.36). The median survival time was 8 years shorter in TS compared to controls.

CONCLUSIONS: The increased mortality in TS was mainly driven by aortic dissections in the young and by heart diseases in the older. Healthcare professionals should prioritize detection and monitoring, with emphasis on cardiovascular diseases.

Background: Guidelines in healthcare should be evidence-based, satisfy patient needs and improve patient outcome.

Methods: We performed a cost-utility analysis in Graves' disease (GD) and estimated incremental costs after the introduction of a national guideline adding the Graves' Recurrent Events After Therapy (GREAT) score with genetic determinants (GREAT+) to predict recurrence, a thyroid nurse, preoperative calcium/vitamin D treatment and thyroid-stimulating immunoglobulins.

Findings: Antithyroid drugs (ATDs) were less costly, achieved 0.88 quality-adjusted life years (QALYs) over 8 years and dominated over radioactive iodine (RAI) treatment. The relevant incremental cost-effectiveness ratio was ATD versus thyroid surgery (Tx). Tx was more costly than ATD but was also more effective. The incremental cost-effectiveness ratio was equal to 40,488 Euro per QALY gained. In recurrent GD, the QALY weight for surgery after ATD was 0.76 compared with 0.79 when surgery was the initial treatment. If individuals requiring surgery could be identified at start of first treatment, QALYs would be higher (6.32) and the cost lower (13,945 Euro). The net cost increase after the new guideline was 17.6%, which was partially an effect from more time being spent with the thyroid nurse. If the GREAT+ score was also applied, the total increased net cost was 14.8% if 24% of the tested patients changed treatment to Tx.

Interpretation: Tx was more cost-effective than RAI when ablative treatment is advocated. Prediction score for recurrence directing patients to earlier Tx is cost-effective and enables the introduction of a specialist thyroid nurse. Health economic evaluations should accompany future guidelines.

C-peptide has a complex role in human physiology, but its effects are not fully understood. Studies have shown a protective impact against diabetic complications, but also that C-peptide levels associate with cardiovascular events. Among the many applications to assess cardiovascular risk, circulating lipids are widely used, and one of the strongest biomarkers is apolipoprotein B. The aim of this investigation was to study the association of C-peptide with markers of metabolic, inflammatory, or cardiovascular alterations in a limited group of healthy individuals. Body mass index (BMI), lipids, and other plasma markers were studied in 28 consecutive healthy individuals within the age of 30-50 years. The results showed significant positive correlations between C-peptide and BMI (r = 0.498; p = 0.007); hsCRP (r = 0.530; p = 0.004); triglycerides (r = 0.530; p = 0.005); cholesterol (r = 0.507; p = 0.006), LDL-cholesterol (r = 0.550; p = 0.002), LDL/HDL ratio (r = 0.460; p = 0.014); apoB (r = 0.622; p < 0.001), apoB/apoA1 ratio (r = 0.563; p = 0.002); and non-HDL cholesterol (r = 0.566; p = 0.002). According to BMI values, 16 of the 28 individuals were overweight (BMI >25.0 kg/m2). If overweight individuals were excluded, C-peptide did only correlate with apoB (r = 0.636; p = 0.026). To conclude, C-peptide within normal levels associate with BMI and atherogenic lipids in healthy individuals, and apoB associate with C-peptide even at normal weight. These results suggest that C-peptide can be an early additional cardiovascular risk marker.

Objective: Autoimmune Addison's disease (AAD) is associated with reduced health-related quality of life and possibly reduced employability. The aim of this study was to assess differences in income and work loss between patients with AAD and matched comparators.

Design: Nationwide, cross-sectional register-based study.

Methods: By linking the Swedish Addison Register and national health registers, we identified working age (18-64 years) individuals with AAD and general population comparators (matched 1:5 by sex, age, and county of residence). We assessed differences in taxable earnings and disposable income through quantile regression and differences in work loss through linear regression during 2019.

Results: We identified 1140 cases with AAD and 5700 comparators (mean age 46.1 years, 48.4% men). Type 1 diabetes was prevalent in 15.7% and 1.1%, respectively. Work loss was higher in AAD; adjusted mean difference 14.4 days; 95% CI, 8.6-20. The adjusted median differences in taxable earnings and disposable income were non-significant overall at -617 (95% CI; -2317 to 1083) and -405 (95% CI; -1417 to 607) . However, significantly lower taxable earnings and disposable income were found among patients with short education: -5303 (95% CI; -9603 to -992) and -3754 (95% CI; -6486 to -1022) , or concomitant type 1 diabetes: -5808 (95% CI; -9937 to -1690) and -3349 (95% CI; -6203 to -506) .

Conclusion: Patients with AAD had more work loss, yet overall similar taxable earnings and disposable incomes versus comparators. Patients with AAD with shorter education or type 1 diabetes were most socioeconomically vulnerable.

AIMS: To investigate the effect of early childhood infections and antibiotic use on the risk of type 1 diabetes in a general population cohort.

RESEARCH DESIGN AND METHODS: The All Babies In Southeast Sweden (ABIS) cohort followed 16 428 children from birth. Questionnaires collected at 1 year (n=11 093), 3 years (n=8 890) and 5 years of age (n=7 445) included data on infections and antibiotic use and were validated against national registers. After a mean follow-up of 25 years, 168 individuals have been diagnosed with type 1 diabetes (1.0% of the original cohort, aged 1-24.5 years).

RESULTS: There were few significant differences in type or frequency of early childhood infections or antibiotic use between cases with type 1 diabetes and the reference group (remaining individuals who did not develop type 1 diabetes) after adjusting for sex, heredity and socioeconomic status. A small number of type 1 diabetes children (4.8% compared to 0.8% of the reference group) reported six or more episodes of gastroenteritis in the 1-3-year age group, resulting in an adjusted odds ratio (aOR) of 8.21; 95% CI 2.70-25.01, p<0.001. Cases of type 1 diabetes with an increased genetic risk (n=91) reported fewer episodes of the common cold between 1 and 3 years of age compared to the reference group (aOR 0.27; 0.13-0.58, p<0.001). Individuals with type 1 diabetes without risk-associated HLA alleles (n=14) reported a higher frequency of pneumonia in the 1-3- and 3-5-year age group (aOR 26.08; 6.29-108.17, p<0.001 and aOR 35.63; 4.10-309.96, p=0.001 respectively), and had more viral and total infections registered in the National Patient Register from 0-5 years (aOR 5.72; 1.59-20.57, p=0.008 and aOR 18.71; 1.95-179.55, p=0.01).

CONCLUSIONS: Childhood infections could increase the risk of developing type 1 diabetes in a small group of individuals without risk-associated HLA alleles, but this was not seen in the majority with HLA-risk. More research is required for this overlooked population, including screening and prevention trials. The association to frequent gastrointestinal infections in the first years of life needs to be reproduced in other studies to be confirmed.

Totalt 433 termin 11-studenter vid 6 lärosäten svarade på hur läkarprogrammet förberett dem för evidensbaserat patientarbete.

Drygt 7 av 10 uppgav att de fått träna på att granska vetenskapliga artiklar enligt mall, men färre att de tränat på andra moment i en systematisk översikt.

Medianstudenten hade 3 av 5 rätt på kunskapsfrågor relaterade till HTA, men en fall–kontrollstudie, ett skogsdiagram och begreppet kostnadseffektivitet tolkades ofta på fel sätt.

Undervisning i HTA samt poänggivande moment i tillämpad evidensbaserad medicin under kliniska terminer var förknippade med upplevelsen att läkarprogrammet gett tillräcklig färdighet i hur man baserar patientarbete på vetenskap.

Several of the requirements for obtaining a medical degree according to the Swedish Higher Education Ordinance illustrate the scientific basis of the profession, and systematic reviews as well as health technology assessments (HTA) constitute cornerstones in evidence-based medicine. In this study, medical students' experience of scientific education related to the profession was explored, and their knowledge achieved was sampled by five multiple-choice questions (MCQ). A total of 433 out of 641 students attending the final semester in six medical schools in Sweden participated (response rate: 68%). Most of them experienced that a majority of the scientifically related learning outcomes for the medical degree had been adequately examined. Regarding the steps of a systematic review, 60% stated that they had been trained to define a specific research question, 64% to find relevant literature according to such a specific research question, 72% to assess scientific articles according to a checklist, 40% to compile results from several studies, and 35% to assess the certainty of evidence according to GRADE. Only 6% stated that they had received education regarding HTA, a factor that was strongly associated with students' perception that they had obtained adequate skills regarding how patient work is based on scientific evidence (adjusted odds ratio [OR] 14.1; 95% CI 1.80-110). Such an association was also found for credit-awarded hands-on evidence-related learning activities during clinical courses (OR 2.72; 95% CI 1.02-7.24). The median student answered 3 of 5 MCQs correctly. The results of a case/control study, a forest plot, and the concept of cost-effectiveness were frequently interpreted erroneously. In conclusion, several aspects of the scientific basis for professional life as a medical doctor seem to be well covered in the medical degree program, whereas others deserve increased attention.

PURPOSE: Patients with primary adrenal insufficiency (PAI) require mineralocorticoid replacement therapy in addition to glucocorticoids. These therapies should be considered in combination because most glucocorticoids also possess mineralocorticoid activity. We aimed to investigate the relationship between fludrocortisone and hydrocortisone-equivalent dosing in patients with PAI.

METHODS: Data were obtained from the European Adrenal Insufficiency Registry (EU-AIR), a multinational, multicenter, observational study conducted between August 7, 2012, and October 31, 2020, in endocrinology centers in Germany, Italy, the Netherlands, Sweden, and the UK. Patients with PAI (excluding congenital adrenal hyperplasia or known hypertension) and treated with immediate-release hydrocortisone (IRHC), modified-release hydrocortisone (MRHC), or cortisone acetate were included. The relationship between hydrocortisone-equivalent and fludrocortisone doses and mineralocorticoid potency corrected for body surface area (BSA) was examined.

RESULTS: Overall, 670 (mean age: 46.2 years; 453 [67.6%] women) of 924 patients with PAI in EU-AIR were analyzed. Of those who received at least one dose of fludrocortisone (n = 350), 45 patients (12.9%) were receiving hydrocortisone-equivalent doses/BSA of ≤ 10 mg/day/m2, 170 patients (48.6%) > 10-15 mg/day/m2, and 133 patients (38.0%) > 15 mg/day/m2. No clear associations were found between total daily fludrocortisone dose/BSA and hydrocortisone-equivalent dose/BSA, or between combined mineralocorticoid potency/BSA and systolic or diastolic blood pressure and sodium or potassium levels. Higher systolic blood pressure was found in IRHC than MRHC groups.

CONCLUSIONS: Fludrocortisone prescription in PAI appears to be independent of glucocorticoid replacement therapy. IRHC and MRHC might differ in mineralocorticoid effect owing to different pharmacokinetic profiles.

CLINICAL TRIAL REGISTRATION: NCT01661387.

Steroid hormone concentrations reflect diverse physiological and pathological processes and have been recognized as valuable biomarkers for disease, with growing interest in their potential for patient stratification in precision medicine. Salivary steroid concentrations should reflect the free (biologically active) steroids in circulation, as steroids in the bloodstream passively diffuse to saliva. This allows for the direct measurement of free steroids without transporter protein-bound hormones (inactive form). However, implementation of salivary steroid quantification in larger studies remains limited by challenges associated with sample preparation. We began by reviewing the literature on relevant sample preparation approaches and identified commonly used 96-well solid phase extraction (SPE) methods for further evaluation. Three sample preparation methods were selected and assessed in terms of internal standard recovery and matrix effects, and their response was also compared using electrospray (ESI) versus UniSpray ionization (USI) liquid chromatography-tandem mass spectrometry (LC-MS/MS). We demonstrate a sensitive and rapid high-throughput method with Oasis HLB mu Elution SPE of 200 mu L saliva in 96-well format and USI-LC-MS/MS for major steroids (testosterone, androstenedione, cortisone, cortisol, and progesterone) in saliva. The method achieved optimal recovery (77%), matrix effects (33%), and sensitivity with detection limits (MDL) ranging between 1.1 and 3.0 pg/mL and linearity (r2 = 0.99). Intra-plate and inter-plate coefficient of variation (CV) was below 7% and 20% using USI. USI provided a higher (2.0-2.8-fold) response than ESI and higher signal-to-noise ratio (S/N). The method was then applied to 97 authentic saliva samples (41 male and 56 female) and significant correlations between age and BMI, and androgen levels were observed in both sexes. The proposed 96-well SPE USI-LC-MS/MS method is well-suited for determining steroid hormones in saliva with potential usefulness in large-scale studies and clinical settings.

OBJECTIVE: To explore teaching- and assessment-related factors that predict medical students' perceived attainment of sufficient skills to incorporate scientific evidence into patient care.

METHODS: An anonymous questionnaire was distributed to final-semester students in six medical programs in Sweden. The students were asked to rate statements concerning the extent to which 11 national degree outcomes related to the scientific basis of medicine (scholarly degree outcomes) had been adequately assessed during the program; their perceived preparedness for evidence-based patient care; and training during the program regarding the components of a systematic review/health technology assessment (HTA).

RESULTS: In total, 433 students (median age: 25 years [interquartile range: 24‒28], 59% female) participated in the study (response rate: 68%). A multivariate analysis indicated that experienced adequate assessment on a single scholarly degree outcome (i.e., "Demonstrate knowledge of the scientific foundation of medicine and insight into current research as well as knowledge of the link between science and proven experience") predicted the students' perception of having developed sufficient skills in incorporating scientific evidence into patient care (odds ratio: 6.17 [95% confidence interval: 3.10; 12.3]). The educational content predictors of this perception included the teaching of HTA (11.3 [1.44; 89.5]) and training regarding two components of a systematic review/HTA: appraising scientific articles using checklists (2.46 [1.23; 4.90]) and assessing organizational aspects related to the introduction/withdrawal of a health technology (2.65 [1.05; 6.67]). The presence of hands-on, credit-bearing, evidence-based medicine (EBM)-related learning activities during clinical courses was also predictive (4.68 [1.69; 13.0]).

CONCLUSIONS: This study highlights important educational activities that prepare medical students to incorporate scientific evidence into patient care: (i) adequate assessment of key content regarding scholarly outcomes, including the scientific foundation of medicine; (ii) learning activities about HTA and the systematic review process; and (iii) hands-on application of EBM-related learning activities integrated into clinical courses.