Per Medbøe Thorsby

• Jorde, Rolf; Thorsby, Per Medbøe & Grimnes, Guri (2026). Low Prevalence of Exploratory Biochemical Patterns Compatible with Osteomalacia in a Large Cohort of Participants with Low Serum 25-Hydroxyvitamin D Levels. Calcified Tissue International. ISSN 0171-967X. 117(1). doi: 10.1007/s00223-026-01612-9. Full text in Research Archive Show summary

  The threshold for vitamin D deficiency is mainly based on osteomalacia prevention. Osteomalacia is diagnosed by bone biopsy, but may potentially also be identified biochemically. Our objective was to examine the prevalence of exploratory biochemical patterns compatible with osteomalacia in a population with low vitamin D status, as well as the effect of vitamin D supplementation on the biochemical parameters. The study was cross-sectional followed by a randomized controlled trial (trial registration number: NCT02750293). The participants were recruited from the population-based Tromsø study. Plasma parathyroid hormone, serum calcium, alkaline phosphatase and bone-specific alkaline phosphatase were measured. 423 participants were included in the cross-sectional part and 382 completed the randomized controlled trial (194 given vitamin D (100,000 IU as a loading dose followed by 20,000 IU per week for four months) and 188 given placebo). The mean serum 25-hydroxyvitamin D level in the cohort was 34 nmol/L. None of the participants had a combination of high (above reference range) serum parathyroid hormone, high alkaline phosphatase, and low (below reference range) serum calcium. With the most permissive exploratory biochemical pattern the prevalence was 8.3%. In the intervention study vitamin D significantly reduced plasma parathyroid hormone and alkaline phosphatase and increased serum calcium as compared to placebo. In conclusion, the prevalence of the explored biochemical patterns compatible with ostemalacia was low and strongly dependent on the analytical thresholds applied. In the absence of validation against bone histomorphometry, these findings cannot determine the prevalence of osteomalacia or establish an appropriate serum 25OHD threshold.

• Sivanesan, Shivanthe; Ramberg, Håkon; Kristiansen, Thomas; Thapa, Suraj; Bjøre, Marthe & Berge, Viktor [Show all 15 contributors for this article] (2026). Perioperative propranolol during robotic-assisted radical prostatectomy: A randomised, double-blind, placebo-controlled, pilot trial (PeP-RALP). BJUI Compass. 7(9). doi: 10.1002/bco2.70267.
• Zykova, Svetlana; Plaksienko, Anna; Solevåg, Anne Lee; Brigtsen, Anne Karin; Michelsen, Trond Melbye & Sørbye, Ingvil Krarup [Show all 12 contributors for this article] (2026). Neonatal reference intervals for salivary steroids: focus on prematurity, stressful events and perinatal betamethasone. Frontiers in Pediatrics. 14. doi: 10.3389/fped.2026.1808446. Full text in Research Archive
• Westbye, Alexander Bauer; Dahll, Louise J. Koren; Bredahl, May Kristin Lyamouri; Thorsby, Per Medbøe & Hammerstad, Sara Salehi (2026). Thyroxine Treatment of Adult RTHα Patients: Safety, Efficacy, and Metabolomic Changes. Thyroid. ISSN 1050-7256. 36(7), p. 788–794. doi: 10.1177/10507256261460201. Full text in Research Archive Show summary

  Background: Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder with symptoms of hypothyroidism, but normal or close-to-normal thyroid function tests. Treatment with levothyroxine (L-T4) may be beneficial. This study investigated the efficacy, safety and biochemical changes of high-dose L-T4 and liothyronine (L-T3) treatment. Methods: Four RTHα (Ala263Val) patients were treated with L-T4 (1.75 µg/kg) in a pilot open-label study and monitored for three years. Quality of life (QoL) was assessed using ThyPro. Analysis of auxiological- and biochemical-parameters, bone mineral density (BMD) and exploratory metabolomics was performed. A partial replacement of L-T4 with L-T3 was attempted. Results: Treatment with L-T4 increased FT4, FT3, and rT3 to supraphysiological concentrations (relative to reference intervals) and suppressed thyroid-stimulating hormone with no adverse effects. Heart rate, bone markers, and sex hormone-binding globulin transiently increased. Several classes of lipids were reduced. BMD appeared unaltered. Patients reported improved QoL. One patient presented a short non-sustained ventricular tachycardia on L-T3 + L-T4. Conclusions: L-T4 treatment of adult RTHα patients was safe and improved QoL in adherent patients.

• Westbye, Alexander Bauer; Kelp, Oskar; Ye, Yilu; Bergmann, Marianne Lerbæk; Aas, Finn Erik & Dahl, Sandra Rinne [Show all 7 contributors for this article] (2026). Simultaneous quantitation of free testosterone and free thyroid hormones in human serum by equilibrium dialysis LC-MS/MS. Analytica Chimica Acta. ISSN 0003-2670. 1401. doi: 10.1016/j.aca.2026.345349. Full text in Research Archive Show summary

  Background Testosterone (Te) and the thyroid hormones (THs) thyroxine (T4) and triiodothyronine (T3) are key endocrine hormones regulating development, metabolism and reproductive function. The free (not protein-bound) hormone concentrations more accurately reflect biological activity than total levels. Free hormone measurements are therefore used for clinical decision making in many contexts. Mass spectrometry (MS)-based methods following equilibrium dialysis (ED) are considered “gold standard” for free hormone quantification. Unfortunately, few clinical laboratories offer such measurements today. Results A 96-well format ED-LC-MS/MS method incorporating isotope-dilution for simultaneous quantitation of free Te, free T4 and free T3 in clinical samples that used offline (parallel) sample-preparation was successfully developed and validated. The method covered clinically relevant ranges, and clinical samples with a wide concentration range were analyzed to perform a comparison to existing (immunoassay or calculation) methods. Free hormone concentration in 20 healthy blood donors is reported. Significance This method allows direct quantitation of both free testosterone and free thyroid hormones in human samples at clinically relevant concentrations. It can be implemented alongside existing LC-MS/MS methods in specialized clinical laboratories to support improved endocrine assessment and clinical decision making.

• Aas, Finn Erik; Westbye, Alexander Bauer; Husøy, Magnus A Rognlien; Kelp, Oskar; Zykova, Svetlana & Thorsby, Per Medbøe (2026). Indirect reference intervals for thyroid function tests: refineR, RefLim and effects of pathological test results. Clinical Biochemistry. ISSN 0009-9120. 142. doi: 10.1016/j.clinbiochem.2026.111101. Full text in Research Archive Show summary

  Background: Biochemical tests with reference intervals (RIs) are extensively used in medicine. RIs should reflect the population tested, and indirect methods for RI construction are increasingly used. Thyroid function tests (TFTs) are used to diagnose and monitor thyroid disorders, that are especially common among women. We report investigations into factors that influence indirect TFT RIs using real world data. Methods: Indirect RIs were calculated (refineR and RefLim) for two laboratories with very different proportions of pathological results for thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3), all measured on Abbott Alinity i. For one laboratory total thyroxine (TT4) and total triiodothyronine (TT3) were also investigated. Effects of pathological results on indirect RIs were investigated and indirect RIs were compared to direct RIs from Abbott and from a reference population (HUNT4). Results: Some TFT RIs differed markedly between the two laboratories, but removal of suspected pathological results reduced the discrepancy. Choice of algorithm for indirect RIs influenced the RIs, and indirect RIs were wider than the direct RIs from HUNT4. Most of our calculated RIs - from indirect (real world data) or direct (HUNT4) methods - were markedly narrower than Abbott-provided RIs, particularly for FT4 and FT3. Conclusions: Indirect RIs for TFT are easily calculated but are affected by several factors that laboratories should be aware of. Manufacturer-provided RIs can differ markedly from in-house RIs.

• Thorsby, Per Medbøe; Dahl, Sandra Rinne; Smetop, Tone; Lindholm, Tone Hæg & Zykova, Svetlana (2025). Stressless sampling to improve diagnostics of catecholamine excess: new assay to determine metanephrines in saliva. Endocrine Connections. 14(5). doi: 10.1530/ec-25-0023. Full text in Research Archive Show summary

  Determination of metanephrines in saliva has been reported as a pain- and hazard-free alternative to plasma-based tests with a potential to reduce false-positive results during diagnostic work-up for neuroendocrine tumours. No validated method has, however, been made available in the published literature so far. The aim of this work was to develop an LC-MS/MS method for the measurement of metanephrine, normetanephrine and 3-methoxytyramine in human saliva. As hyposalivation represents a real-life challenge in situations with catecholamine excess, special effort was made to minimise specimen volume and to make the assay suitable also for paediatric and geriatric populations. The method validation was performed according to relevant guidelines and included recovery from three different collection swabs (Salivette, SalivaBio and Salimetrics). Selectivity, interferences, matrix effects, limits of quantification, linearity of calibration, sample volume, trueness, within-run and total analytical repeatability, robustness, carry-over and stability were evaluated. A sample volume as low as 20 μL was acceptable for all analytes, but 50 μL sample volume gave lower LLOQ, higher accuracy and better precision. Total analytical variation was <15% and the minimum turnaround time was 3 h. Among the sample collection devices tested, highest recovery was achieved with SalivaBio (93–104%). Metanephrines were stable in saliva when stored at ambient temperature for 6 h, and tolerated at least 1 week of freezing at −20°C. The non-invasiveness, ease of specimen collection, better stability of analytes compared to plasma and analytical performance make the method relevant for both research and diagnostics of states with catecholamine excess. Plain language summary A new method to measure breakdown products of adrenalin, noradrenalin and dopamine in saliva is proposed. The main advantage of saliva test compared to traditional blood-based assays is that specimen can be collected without stress and pain. The method can improve diagnostics of hormone-producing tumours by reducing likelihood of hormone elevations due to stress and pain (false positive results) and avoiding hazards associated with blood collection, particularly in children.

• Westbye, Alexander Bauer; Dizdarevic, Lili Leko; Dahl, Sandra Rinne; Asprusten, Emil Andreas; Bliksrud, Yngve Thomas & Lövgren-Sandblom, Anita [Show all 9 contributors for this article] (2025). A sterol panel for rare lipid disorders: sitosterolemia, cerebrotendinous xanthomatosis and Smith-Lemli-Opitz syndrome. Journal of Lipid Research. ISSN 0022-2275. 66(1). doi: 10.1016/j.jlr.2024.100698. Full text in Research Archive Show summary

  Disease-specific sterols accumulate in the blood of patients with several rare lipid disorders. Biochemical measurement of these sterols is important for correct diagnosis and sometimes monitoring of treatment. Existing methods to measure sterols in blood, particularly plant sterols, are often laborious and time consuming. Partly as a result, clinical access to sterol measurements is limited in many parts of the world. A simple and rapid method to extract free sterols from human serum and quantitate their concentration using isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization was developed. The method was designed to be compatible with routine workflows (e.g., 96-well format) in a clinical lab and extensively validated. Serum from at least 125 controls were analyzed and used to estimate the upper reference limits for sitosterol, campesterol, stigmasterol, desmosterol, 7-dehydrocholesterol (7DHC), lathosterol, and cholestanol. Serum from patients with the rare lipid disorders sitosterolemia (n = 7), Smith-Lemli-Opitz syndrome (SLOS; n = 1), and cerebrotendinous xanthomatosis (CTX; n = 1) were analyzed. All seven sitosterolemia patients had greatly elevated levels of free plant sterols (sitosterol, campesterol, and stigmasterol) compared to the controls. The SLOS serum contained massively increased concentrations of 7DHC. CTX serum contained greatly increased concentrations of cholestanol, as well as 7DHC and lathosterol. Spiking experiments indicated that the method is likely also useful for the diagnosis of desmosterolosis and lathosterolosis. The reported method is a relatively simple and fast LC-MS/MS method capable of quantitating diagnostically important sterols and differentiated patients with three rare lipid disorders from controls.

• Kvammen, Janne Anita; Thomassen, Rut Anne; Buechner, Jochen; Myklebust, Tor Åge; Thorsby, Per Medbøe & Bollerslev, Jens [Show all 9 contributors for this article] (2025). Vitamin D status in children undergoing allogeneic hematopoietic stem cell transplantation: A prospective exploratory study. Journal of Pediatric Gastroenterology and Nutrition - JPGN. ISSN 0277-2116. 80(6), p. 1007–1017. doi: 10.1002/jpn3.70028. Full text in Research Archive Show summary

  Objectives Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with nutritional risks. This study describes vitamin D status and intake in children undergoing HSCT and compares results to healthy children. Methods In a prospective observational study, vitamin 25(OH)D and 1,25(OH)2D were assessed at hospital admission before HSCT (baseline), at 3-month and 1-year post-transplant. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L. A 4-day diet record assessed vitamin D intake at 3-months and 1-year. Healthy children were assessed once. Results Twenty-eight HSCT patients (mean age: 10.3-years, standard deviation [SD]: 4.0) and 50 healthy children (mean age: 10.0-years, SD: 3.6) were included. Vitamin D deficiency was more prevalent in patients at baseline (36%, p < 0.001) and 3-months (24%, p = 0.007) but not at 1-year (14%, p = 0.084) than in healthy children (2%). Median 1,25(OH)2D was significantly lower than in healthy children at the two first visits (p < 0.001) but not at 1-year (p = 0.198). Median vitamin D provision was higher at 3-months (18.1 µg/day) and 1-year (25 µg/day) compared to healthy children (5.3 µg/day, p < 0.001). Conclusions Children undergoing HSCT were at a high risk of vitamin D deficiency at baseline and 3-month post-transplant, but not at 1-year compared to healthy children. Vitamin D intake was higher after transplantation than in healthy children. These findings indicate that vitamin D requirements are elevated in HSCT patients, emphasizing the need for monitoring and adequate supplementation.

• Mosti, Mats Peder; Aagård, Norun; Stunes, Astrid Kamilla; Brobakken, Cathrine Langlie; Brevig, Martin Siksjø & Gustafsson, Miriam K. [Show all 9 contributors for this article] (2025). Acute effects of a single bout of strength and Eendurance exercise on vitamin D metabolites in young adults. Medicine & Science in Sports & Exercise. ISSN 0195-9131. 57(6), p. 1189–1201. doi: 10.1249/MSS.0000000000003658. Full text in Research Archive
• Birkeland, Eline; Bamigbetan, Wuraola Aduke; Molven, Kristine Duus; Thorsby, Per Medbøe; Gulseth, Hanne Løvdal & Aas, Anne-Marie [Show all 7 contributors for this article] (2025). Can supplements with prebiotic fibres positively influence bone health in type 2 diabetes? Insights from a randomised controlled crossover trial. Archives of Osteoporosis. ISSN 1862-3522. 20(1). doi: 10.1007/s11657-025-01556-x. Full text in Research Archive Show summary

  Summary Inulin-type fructans did not significantly improve serum levels of calcium, magnesium, vitamin D, or bone turnover markers in people with type 2 diabetes (T2D). However, interactions between gut microbiota and bone health were suggested, indicating the need for further research in this population. Background Evidence suggests that a healthy gut microbiome benefits bone health, especially in immunocompromised populations like the elderly and people with T2D. Objective We investigated the effect of prebiotics (inulin-type fructans) on serum concentrations of calcium, magnesium, 25(OH) vitamin D, and the bone turnover markers N-terminal propeptide of type 1 collagen (P1NP), and C-terminal telopeptide of type 1 collagen (CTX-1) in people with T2D. Design Participants (29) were treated for 6 weeks with 16 g inulin-type fructans and 16 g control supplement (maltodextrin) in randomised and double-blind crossover design, with a 4-week washout between treatments. Results Compared to the control, inulin-type fructans did not significantly affect serum concentrations (mean ± SEM) of calcium (0.05 ± 0.02 mmol/L vs. 0.02 ± 0.03 mmol/L, p = 0.324), magnesium (0.02 ± 0.01 mmol/L vs. 0.00 ± 0.01 mmol/L, p = 0.352), 25(OH) vitamin D (-3.60 ± 1.94 nmol/L vs. -2.00 ± 1.97 nmol/L, P = 0.564), P1NP (0.81 ± 0.95 ug/L vs. -0.89 ± 0.97 ug/L, p = 0.210), or CTX-1 (-0.01 ± 0.01 ug/L vs. 0.00 ± 0.01 ug/L, p = 0.438). However, post hoc analyses of correlations between changes support that cross-talk between the human host and gut microbiota may influence bone health in this population. Conclusion This study does not support that inulin-type fructans may improve serum levels of calcium, magnesium, or 25(OH) vitamin D, nor that they affect bone turnover markers in people with T2D over 6 weeks. Interactions between microbiota and bone health in this population warrants further investigations.

• Vetter-Lang, Sebastian G.; Huber, Nikolaus; Loe, Leif Egil; Evans, Alina; Kumpula, Jouko & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2025). Getting used to it? Stress of repeated management procedures in semi-domesticated reindeer. BMC Veterinary Research. 21(1). doi: 10.1186/s12917-025-04718-8. Full text in Research Archive Show summary

  Background Extensive animal production systems, such as reindeer husbandry may represent a system to further study the context dependence of stress responses and the potential implications for animal welfare as research on food animal stress and welfare has so far primarily focused on animals in intensive animal production systems while animals from extensive production systems, such as reindeer, are yet underrepresented. We investigated short- and longer-term stress responses to repeated herding, handling and restraint and its potential effect on animal welfare in semi-domesticated adult female reindeer (Rangifer tarandus tarandus). We also assessed seasonal differences and the potential effect of the additional stressor of calf removal using serum concentrations of glucocorticoids (cortisol, cortisone and corticosterone), their precursors (11-desoxcortisol, 17-α-hydroxyprogesterone and deoxycorticosterone) and catecholamine metabolites (metanephrine and normetanephrine) in combination with the immunological stress proxy leukocyte coping capacity (LCC) and rectal temperature. Additionally, we assessed the interconnections among different stress indices and their suitability as stress indicators to evaluate handling-induced stress in reindeer, where rectal temperature, other than serum cortisol levels, emerged as a robust and integrative stress parameter. Results Herding, handling, and restraint elicited a marked and seasonally different short-term stress response with higher stress mediator levels in winter. Further, females who had their calf removed shortly after parturition showed increased stress levels based on LCC. The repeated exposure to the same stressors led to a habituation, with decreasing levels of stress indices to the procedure in both seasons. This outcome implies that reindeer females in the present study were able to cope well with repeated manipulations and that this intensification may not compromise animal welfare. Notably, the traditional stress index body temperature correlated with various stress indices encompassing the HPA axis response (cortisol and corticosterone in summer and additionally cortisone and 11-deoxycortisol in winter), the sympathetic-adrenal-medullary system (metanephrine) as well as the immunological response to stress (LCC), in both seasons. Conclusion Our results emphasise body (rectal) temperature as a robust and integrative stress parameter in the context of our study. Our findings add to a foundation for evaluating available stress indices in different individual and environmental contexts and may contribute to improved animal management practices aimed at reducing stress levels and enhancing animal welfare.

• Gregersen, Ida; Scarth, Morgan Elizabeth; Abdullah, Rang; Thorsby, Per Medbøe; Hauger, Lisa Evju & Haugaa, Kristina Ingrid Helena Hermann [Show all 14 contributors for this article] (2024). Elevated interleukin 8 and matrix metalloproteinase 9 levels are associated with myocardial pathology in users of anabolic-androgenic steroids. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 31(12), p. 1469–1476. doi: 10.1093/eurjpc/zwae126. Full text in Research Archive Show summary

  Aims In the current paper, we aim to explore the effect of both current and former long-term anabolic-androgenic steroid (AAS) use on regulation of systemic inflammatory markers and mediators of extracellular matrix (ECM) remodelling and their association with hormones and echocardiographic myocardial pathology in weightlifters. Methods and results In a cross-sectional study, 93 weightlifting AAS users, of whom 62 were current and 31 were past users, with at least 1-year cumulative AAS use (mean 11 ± 7 accumulated years of AAS use), were compared with 54 non-using weightlifting controls (WLCs) using clinical interview, blood pressure measurements, and echocardiography. Serum levels of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF), interferon (IFN)-γ, growth differentiation factor (GDF)-15, and matrix metalloproteinase (MMP)-9, sex hormones, and lipids were analysed. It was found that serum levels of IL-8, GDF-15, and MMP-9 were significantly increased in current AAS users compared with former users and WLCs. Matrix metalloproteinase 9, but not IL-8, correlated consistently with sex hormone levels, and sex hormone levels correlated consistently with mean wall thickness, in current users. Moreover, HDL cholesterol was significantly lower in current vs. former AAS users and significantly inversely correlated with MMP-9 in current users. Further, in current users, MMP-9 and IL-8 correlated with markers of myocardial strain, and MMP-9 also correlated with indices of cardiac mass, which was not seen in former users. Mediation analyses suggested that MMP-9 could partly explain hormone-induced alterations in markers of myocardial damage in current users. Conclusion Long-term AAS is associated with increased levels of markers of inflammation and ECM remodelling, which seems to have a hormone-dependent (MMP-9) and a hormone-independent (IL-8) association with markers of myocardial dysfunction.

• Henriksen, Hans Christian Bordado; Havnes, Ingrid Amalia; Jørstad, Marie Lindvik; Abdullah, Rang; Thorsby, Per Medbøe & Hauger, Lisa Evju [Show all 10 contributors for this article] (2024). Treatment-seeking behavior and cardiovascular morbidity among men with anabolic-androgenic steroid use: A cross-sectional study. Scandinavian Journal of Medicine & Science in Sports. ISSN 0905-7188. 34(1). doi: 10.1111/sms.14554. Full text in Research Archive Show summary

  Aims To determine associations between anabolic-androgenic steroid (AAS) use-related morbidity including cardiovascular disease (CVD) and engagement to health services. Methods In this cross-sectional study, 90 males with at least 12 months cumulative current or former use of AAS were included. The participants were divided into a treatment-seeking group (TSG) and a non-treatment seeking group (non-TSG) based on their responses to a self-report web questionnaire. All participants were screened for symptoms that could be indicative of CVD through a clinical interview, and examined with blood samples, blood pressure measurements and transthoracic echocardiography. Results In the total sample (n = 90), mean age was 39 ± 11 years with cumulative AAS use of 12 ± 9 years. Among men in the TSG with current use there were higher prevalence of dyspnoea (50% vs 7%) and reduced left ventricular ejection fraction (LVEF) in conjunction with left ventricular hypertrophy (LVH) (36 vs. 9%) and/or high blood pressure (55% vs. 19%) compared to men in the non-TSG. Among men with current AAS use and established LVEF <50% (n = 25) or LVH (n = 21), 44% (11) and 43% (9) respectively, had never engaged health services due to AAS-related adverse effects. Deviant liver- and kidney parameters were frequently observed in the total sample but without between-group differences. Conclusions Treatment-seeking behavior among current AAS users may be associated with increased levels of dyspnoea and established CVD. Despite objective signs of severe CVD among a substantial amount of study participants, it is of great concern that the majority had never sought treatment for AAS-related concerns.

• Dahl, Sandra Rinne; Bakke, Liv Hanne; Thorsby, Per Medbøe & Zykova, Svetlana (2024). An LC-MS/MS assay for simultaneous determination of 13 steroid hormones and two synthetic steroids in saliva: potential utility for paediatric population and beyond. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 84(7-8), p. 527–534. doi: 10.1080/00365513.2024.2437620. Full text in Research Archive Show summary

  Saliva samples offer the possibility to obtain stress-free non-invasive samples, also for home-testing, especially useful when blood collection is either undesirable or difficult. The aim of this work was to develop an LC-MS/MS method to determine clinically relevant steroid hormones cortisol, cortisone, 11-deoxycortisol, 21-deoxycortisol, 17OH-progesterone, aldosterone, corticosterone, deoxycorticosterone, testosterone, androstenedione, DHEAS, DHEA, 17OH-pregnenolone, betamethasone and dexamethasone. A special effort was made to adapt the method to neonatal population with respect to choice of saliva as matrix, low sample volumes, selection of analytes and multiplexing. Validation included selectivity, interferences, matrix effects, lower and upper limit of quantification, linearity of calibration, dilution of samples, trueness, within-run and total analytical repeatability, robustness, carry-over, stability and recovery from sample collection swab. Ten microliters were acceptable but 50 µL preferable sample volume, except for 21-deoxycortisol. Cortisol, cortisone, aldosterone, 11-deoxycortisol, deoxycorticosterone, dexamethasone, betamethasone, 17OH-pregnenolone and DHEAS could be determined in as little as 2-5µL saliva. Total analytical variation was <15%, except for 17OH-progesterone, deoxycorticosterone, 17OH-pregnenolone, 21-deoxycortisol, androstenedione, DHEA and betamethasone, that could only be determined semi-quantitatively or qualitatively. The minimum turnaround time was 3–4 h. Recovery from the best performing sample collection swab SalivaBio ranged from 83 to 127%. Aldosterone, cortisone and DHEA were more stable in saliva compared to serum when stored at ambient temperature for one week. Corticosterone and 17OH-progesterone needed immediate freezing. The non-invasiveness, small saliva volume requirement, on-swab stability and analytical performance make the method relevant for both research and diagnostics, above all in the setting of neonatal intensive care unit.

• Stunes, Astrid Kamilla; Mosti, Mats Peder; Gustafsson, Miriam K.; Børsting, Torunn; Thorsby, Per Medbøe & Stafne, Signe Nilssen [Show all 7 contributors for this article] (2024). Maternal vitamin A and D status in second and third trimester of pregnancy and bone mineral content in offspring at nine years of age. Frontiers in Endocrinology. 15:1417656, p. 1–14. doi: 10.3389/fendo.2024.1417656. Full text in Research Archive Show summary

  Introduction: Maternal nutritional and vitamin status during pregnancy may have long-term effects on offspring health and disease. The aim of this study was to examine the associations between maternal vitamin A and D status in pregnancy and offspring bone mineral content (BMC) at nine years of age. Methods: This is a post-hoc study of a randomized control trial including 855 pregnant women from two Norwegian cities; Trondheim and Stavanger. The women were randomized into an exercise intervention or standard antenatal care. Mother and child pairs for the present study were recruited from those still living in Trondheim after 8–10 years. Serum vitamin A (retinol) and vitamin D (25(OH)D) were measured in the 2nd and 3rd trimesters of pregnancy, and active vitamin D (1,25(OH)2D) in serum was measured in a subgroup. Spine BMC and trabecular bone score were measured in the children at nine years of age. Associations were analyzed with linear regression models. Results: A total of 119 mother and child pairs were included in the analyses. Vitamin A insufficiency (retinol< 1.05 µmol/L) and vitamin D deficiency (25(OH)D< 50 mmol/L) increased from ~7% to ~43% and from ~28% to ~33%, respectively, from the 2nd to the 3rd trimester. An increase in serum 1,25(OH)2D from the 2nd to the 3rd trimester was observed in the subgroup. There was a negative association between serum retinol in the 2nd trimester and spine BMC in the boys, but not in the girls, when adjusted for maternal and child confounders. No other associations between maternal serum vitamin A or D and BMC in the children were found. Conclusion: We observed a high prevalence of vitamin A insufficiency and vitamin D deficiency during pregnancy. A negative association between mid-pregnancy vitamin A status and spine BMC was observed in boys, but not girls, while no associations were found between maternal vitamin D status and child BMC. The implications of optimal vitamin A and D status in pregnancy for offspring bone health, remains a subject for further investigations.

• Juvodden, Hilde Therese; Alnæs, Dag; Agartz, Ingrid; Andreassen, Ole A.; Server, Andrés & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2024). Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study. Sleep Medicine. ISSN 1389-9457. 116, p. 81–89. doi: 10.1016/j.sleep.2024.02.031. Full text in Research Archive Show summary

  There was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. Methods We included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. Results Patients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. Conclusions Post-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Agartz, Ingrid; Andreassen, Ole & Server, Andrés [Show all 9 contributors for this article] (2023). Larger hypothalamic volume in narcolepsy type 1. Sleep. ISSN 0161-8105. 46(11). doi: 10.1093/sleep/zsad173. Full text in Research Archive Show summary

  Study Objectives: Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%–90% loss of the 50 000–70 000 hypocretin-producing neurons and 64%–94% increase in the 64 000–120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. Methods: We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. Results: The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen’s d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. Conclusions: In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.

• Viste, Rannveig; Follin, Louise Frøstrup; Kornum, Birgitte R.; Lie, Benedicte Alexandra; Viken, Marte Kathrine & Thorsby, Per Medbøe [Show all 9 contributors for this article] (2023). Increased muscle activity during sleep and more RBD symptoms in H1N1-(Pandemrix)-vaccinated narcolepsy type 1 patients compared with their non-narcoleptic siblings. Sleep. ISSN 0161-8105. 46(3), p. 1–14. doi: 10.1093/sleep/zsac316. Full text in Research Archive Show summary

  Abstract Study Objectives Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity. Methods RBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5–15 s); short (0.1–0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed. Results RBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p &amp;lt; 0.001). Patients with undetectable CSF hypocretin-1 levels (&amp;lt;40 pg/ml) had significantly more NREM periodic long muscle activity than patients with low but detectable levels (40–150 pg/ml) (p = 0.047). In siblings, REM and NREM sleep muscle activity indices were not associated with RBD symptoms, other narcolepsy symptoms, or HLA-DQB1*06:02-positivity. H1N1-(Pandemrix)-vaccination status did not predict muscle activity indices in patients or siblings. Conclusion Increased REM and NREM muscle activity and more RBD symptoms is characteristic of NT1, and muscle activity severity is predicted by hypocretin deficiency severity but not by H1N1-(Pandemrix)-vaccination status. In the patients’ non-narcoleptic siblings, neither RBD symptoms, core narcoleptic symptoms, nor the major NT1 risk factors is associated with muscle activity during sleep, hence not indicative of a phenotypic continuum.

• Molteberg, Ellen; Thorsby, Per Medbøe; Kverneland, Magnhild; Iversen, Per Ole; Selmer, Kaja Kristine & Hofoss, Dag [Show all 8 contributors for this article] (2023). Stress biomarkers in adult patients with drug-resistant epilepsy on a modified Atkins diet: A prospective study. Epilepsia Open. 8, p. 1331–1339. doi: 10.1002/epi4.12808. Full text in Research Archive Show summary

  Abstract Objective Ketogenic diets like the modified Atkins diet (MAD) are increasingly used in patients with refractory epilepsy. For epilepsy patients, stress is a well‐known seizure‐precipitating factor. New possibilities for measuring biomarkers of stress are now available. The purpose of this study was to investigate the impact of MAD on endocrine stress biomarkers. Methods Forty‐nine patients with drug‐resistant epilepsy were investigated at baseline and after 12 weeks on MAD. Cortisol and cortisol‐binding globulin (CBG) were measured and free cortisol index (FCI) calculated. We also measured metanephrine, normetanephrine, and methoxytyramine, all markers of epinephrine, norepinephrine, and dopamine, respectively. Changes were analyzed according to sex and antiseizure medications. The different markers at baseline and after 12 weeks of MAD treatment were correlated with seizure frequency and weight loss, respectively. Results The change in total cortisol was modest after 12 weeks on the diet (from 432.9 nmol/L (403.1–462.7)) to 422.6 nmol/L (384.6–461.0), P  = 0.6). FCI was reduced (from 0.39 (0.36–0.42) to 0.34 (0.31–0.36), P  = 0.001). CBG increased during the study (from 1126.4 nmol/L (1074.5–1178.3) to 1272.5 nmol/L (1206.3–1338.7), P  &lt; 0.001). There were no changes in the metanephrines after 12 weeks on the diet. The decrease in FCI was significant only in women, and only observed in patients using nonenzyme‐inducing ASMs. We did not find any correlation between cortisol, CBG, or FCI levels and seizure frequency. Significance After being on MAD for 12 weeks, FCI decreased significantly. The reduction in FCI may reflect reduced stress, but it may also be an effect of increased CBG. The reasons behind these alterations are unknown. Possibly, the changes may be a result of a reduction in insulin resistance and thyroid hormone levels. Treatment with MAD does not seem to influence “fight or flight” hormones.

• Scarth, Morgan; Hauger, Lisa Evju; Thorsby, Per Medbøe; Leknes, Siri; Hullstein, Ingunn Riise & Westlye, Lars Tjelta [Show all 7 contributors for this article] (2023). Supraphysiological testosterone levels from anabolic steroid use and reduced sensitivity to negative facial expressions in men. Psychopharmacology. ISSN 0033-3158. doi: 10.1007/s00213-023-06497-2. Full text in Research Archive Show summary

  Abstract Rationale Anabolic-androgenic steroids (AAS) are used to improve physical performance and appearance, but have been associated with deficits in social cognitive functioning. Approximately 30% of people who use AAS develop a dependence, increasing the risk for undesired effects. Objectives To assess the relationship between AAS use (current/previous), AAS dependence, and the ability to recognize emotional facial expressions, and investigate the potential mediating role of hormone levels. Methods In total 156 male weightlifters, including those with current ( n = 45) or previous ( n = 34) AAS use and never-using controls ( n = 77), completed a facial Emotion Recognition Task (ERT). Participants were presented with faces expressing one out of six emotions (sadness, happiness, fear, anger, disgust, and surprise) and were instructed to indicate which of the six emotions each face displayed. ERT accuracy and response time were recorded and evaluated for association with AAS use status, AAS dependence, and serum reproductive hormone levels. Mediation models were used to evaluate the mediating role of androgens in the relationship between AAS use and ERT performance. Results Compared to never-using controls, men currently using AAS exhibited lower recognition accuracy for facial emotional expressions, particularly anger ( Cohen’s d = −0.57, p FDR = 0.03) and disgust ( d = −0.51, p FDR = 0.05). Those with AAS dependence ( n = 47) demonstrated worse recognition of fear relative to men without dependence ( d = 0.58, p = 0.03). Recognition of disgust was negatively correlated with serum free testosterone index (FTI); however, FTI did not significantly mediate the association between AAS use and recognition of disgust. Conclusions Our findings demonstrate impaired facial emotion recognition among men currently using AAS compared to controls. While further studies are needed to investigate potential mechanisms, our analysis did not support a simple mediation effect of serum FTI.

• Pfabigan, Daniela M.; Frogner, Erik Rimestad; Schéle, Erik; Thorsby, Per Medbøe; Skålhegg, Bjørn Steen & Dickson, Suzanne L. [Show all 7 contributors for this article] (2023). Ghrelin is related to lower brain reward activation during touch. Psychophysiology. ISSN 0048-5772. 61(2). doi: 10.1111/psyp.14443. Full text in Research Archive Show summary

  The gut hormone ghrelin drives food motivation and increases food intake, but it is also involved in the anticipation of and response to rewards other than food. This pre-registered study investigated how naturally varying ghrelin concentrations affect the processing of touch as a social reward in humans. Sixty-seven volunteers received slow caressing touch (so-called CT-targeted touch) as a social reward and control touch on their shins during 3T functional imaging on two test days. On one occasion, participants were fasted, and on another, they received a meal. On each occasion, plasma ghrelin was measured at three time points. All touch was rated as more pleasant after the meal, but there was no association between ghrelin concentrations and pleasantness. CT-targeted touch was rated as the most pleasant and activated somatosensory and reward networks (whole brain). A region-of-interest in the right medial orbitofrontal cortex (mOFC) showed lower activation during all touches, the higher the ghrelin concentrations were. During CT-targeted touch, a larger satiety response (ghrelin decrease after the meal) was associated with higher mOFC activation, and this mOFC activation was associated with higher experienced pleasantness. Overall, higher ghrelin concentrations appear to be related to a lower reward value for touch. Ghrelin may reduce the value of social stimuli, such as touch, to promote food search and intake in a state of low energy. This suggests that the role of ghrelin goes beyond assigning value to food reward.

• Åkerman, Anna-Karin; Sævik, Åse Bjorvatn; Thorsby, Per Medbøe; Methlie, Paal; Quinkler, Marcus & Jørgensen, Anders Palmstrøm [Show all 26 contributors for this article] (2023). Plasma-Metanephrines in Patients with Autoimmune Addison’s Disease with and without Residual Adrenocortical Function. Journal of Clinical Medicine. 12:3602(10), p. 1–10. doi: 10.3390/jcm12103602. Full text in Research Archive Show summary

  Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

• Brekke, Stine Marie; Halvorsen, Silje Torp; Bjørkvoll, Julie; Thorsby, Per Medbøe; Rønnestad, Arild Erland & Zykova, Svetlana [Show all 12 contributors for this article] (2023). The association between infant salivary cortisol and parental presence in the neonatal intensive care unit during and after COVID-19 visitation restrictions: A cross-sectional study. Early Human Development. ISSN 0378-3782. 182. doi: 10.1016/j.earlhumdev.2023.105788. Full text in Research Archive Show summary

  Objectives: Parent-infant interaction in the neonatal intensive care unit (NICU) promotes health and reduces infant stress. During the COVID-19 pandemic, however, NICUs restricted parent-infant interaction to reduce viral transmission. This study examined the potential relationship between pandemic visitation restrictions, parental presence and infant stress as measured by salivary cortisol. Methods: A two-NICU cross-sectional study of infants with gestational age (GA) 23–41 weeks, both during (n = 34) and after (n = 38) visitation restrictions. We analysed parental presence with and without visitation restrictions. The relationship between infant salivary cortisol and self-reported parental NICU presence in hours per day was analysed using Pearson's r. A linear regression analysis included potential confounders, including GA and proxies for infant morbidity. The unstandardised B coefficient described the expected change in logtransformed salivary cortisol per unit change in each predictor variable. Results: Included infants had a mean (standard deviation) GA of 31(5) weeks. Both maternal and paternal NICU presence was lower with versus without visitation restrictions (both p ≤0.05). Log-transformed infant salivary cortisol correlated negatively with hours of parental presence (r = − 0.40, p = .01). In the linear regression, GA (B = -0.03, p = .02) and central venous lines (B = 0.23, p = .04) contributed to the variance in salivary cortisol in addition to parental presence (B = -0.04 p = .04). Conclusion: COVID-19–related visitation restrictions reduced NICU parent-infant interaction and may have increased infant stress. Low GA and central venous lines were associated with higher salivary cortisol. The interaction between immaturity, morbidity and parental presence was not within the scope of this study and merits further investigation.

• Ollila, Hanna M.; Sharon, Eilon; Lin, Ling; Sinnott-Armstrong, Nasa; Ambati, Aditya & Yogeshwar, Selina M. [Show all 411 contributors for this article] (2023). Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy. Nature Communications. 14. doi: 10.1038/s41467-023-36120-z. Full text in Research Archive Show summary

  Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

• Westbye, Alexander Bauer; Aas, Finn Erik; Dahl, Sandra Rinne; Zykova, Svetlana; Kelp, Oskar & Dahll, Louise J. Koren [Show all 7 contributors for this article] (2023). Large method differences for free thyroid hormone assays in the hyperthyroid range can affect assessment of hyperthyroid status: Comparison of Abbott Alinity to Roche Cobas, Siemens Centaur and equilibrium dialysis LC-MS/MS. Clinical Biochemistry. ISSN 0009-9120. 121-122. doi: 10.1016/j.clinbiochem.2023.110676. Full text in Research Archive Show summary

  Background Free T4 (FT4) determination is one of the most commonly performed biochemical tests in endocrinology. Treatment of thyroid dysfunctions is adjusted based on the severity of symptoms and biochemical test results. For Graves’ hyperthyroidism, clinical guidelines recommend using FT4 as a (rough) guide to dose antithyroid drugs, together with other clinical information. It is well known that different platforms and methods give different FT4 results; however, large non-linear method differences at high FT4 concentrations are less well recognized. Current clinical guidelines do not make it clear that method differences in the hyperthyroid range can affect recommendations. Method Serum samples from patients with very low (biochemically hypothyroid) to very high (hyperthyroid) concentrations of FT4 and/or free T3 (FT3) were analyzed using Abbott Alinity and compared to concentrations measured using Roche Cobas, Siemens ADVIA Centaur (FT4 only) and an in-house equilibrium dialysis liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Results Alinity measured markedly lower FT4 and FT3 concentrations compared to the other methods, particularly at high FT4 concentrations. Regression analysis indicated that Alinity FT4 had a non-linear (curved) relationship to FT4 measured by the other methods. The method differences affected guideline-recommended treatments for hyperthyroidism. Conclusion Measured free thyroid hormone concentrations are highly method-dependent, especially at high FT4 concentrations. Clinicians treating hyperthyroid patients should be aware that patients appear much less hyperthyroid from FT4-measurements performed using Alinity compared to Cobas or Centaur. Guideline-recommended antithyroid drug dosages based on FT4 (including multiples of the upper reference range) have to be adjusted to the FT4 method used. FT4 results from different methods should be clearly distinguished (e.g. separate lines) in medical records.

• Dahll, Louise J. Koren; Westbye, Alexander Bauer; Vinorum, Kristin; Sejersted, Yngve; Barøy, Tuva & Thorsby, Per Medbøe [Show all 7 contributors for this article] (2023). Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha. Journal of the Endocrine Society (JES). 7(8). doi: 10.1210/jendso/bvad089. Full text in Research Archive Show summary

  Background: Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably underdiagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood. Cases: We investigated 4 previously untreated Caucasian adult first-degree-related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports. Results: During childhood and adolescence, short stature, short limbs, metacarpals, and phalanges, and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face, and increased head circumference were common features. All individuals complained of tiredness, constipation, and low mood. While thyrotropin (TSH) and free thyroxine (FT4) were within the reference range, free triiodothyronine (FT3) was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low hemoglobin and high LDL/HDL ratio. Conclusion: Investigation of 4 first-degree-related adult patients with untreated resistance to thyroid hormone alpha (RTHα) revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features, as treatment in early childhood may improve outcomes.

• Westbye, Alexander Bauer; Aas, Finn Erik; Kelp, Oskar; Dahll, Louise J. Koren & Thorsby, Per Medbøe (2023). Analysis of free, unbound thyroid hormones by liquid chromatography-tandem mass spectrometry: A mini-review of the medical rationale and analytical methods. Analytical Science Advances (ASA). 4(7-8), p. 244–254. doi: 10.1002/ansa.202200067. Full text in Research Archive Show summary

  Measurement of hormones is important for the diagnosis and management of endocrine diseases. The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are among the most commonly measured hormones in clinical laboratories, and it is the concentration of free (not bound to proteins) thyroid hormones that is clinically most relevant. Free thyroid hormones are commonly measured using automated immunoassays, however, these are known to produce erroneous results due to interferences for some patients. Measurement of free thyroid hormones using equilibrium dialysis or ultrafiltration combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is considered a more accurate and robust method for free thyroid hormone analysis and overcomes many of the limitations of immunoassays. However, LC-MS/MS-based methods are often considered too technically difficult and not amendable to high throughput by clinical chemists and are not offered by many clinical laboratories. This mini-review aims to make it easier for clinical laboratories to implement LC-MS/MS-based measurement of free thyroid hormones. It describes the medical rationale for measuring free thyroid hormones, the benefits of LC-MS/MS-based methods with respect to interferences affecting immunoassay-based methods and physical separation methods. This mini-review highlights important parameters for ultrafiltration and equilibrium dialysis to obtain physiologically relevant free thyroid hormone concentrations and focuses on methods and devices used in clinical chemistry.

• Hansen, Berit M Hjelde; Andresen, Hilde Norsted; Gjesvik, Jonas; Thorsby, Per Medbøe; Nærland, Terje & Knudsen, Stine (2023). Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type1. Sleep Medicine. ISSN 1389-9457. 109, p. 149–157. doi: 10.1016/j.sleep.2023.06.021. Full text in Research Archive Show summary

  Objective/Background Psychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of this study was to evaluate the prevalence of psychiatric disorders and executive dysfunctions, secondly to explore the association between psychiatric comorbidity, executive dysfunctions, subjective and objective sleep measures, and severity of cerebrospinal fluid (CSF) hypocretin-1 deficiency in pediatric narcolepsy type 1 (PNT1). Patients/Methods Cross-sectional study of 59 consecutively included PNT1 patients (age: 6-20 years; 34:25 girls: boys; 54/59 H1N1 (Pandemrix®)-vaccinated). Core narcolepsy symptoms including subjective sleepiness, polysomnography and multiple sleep latency test results, CSF hypocretin-1 levels, psychiatric disorders (by semistructured diagnostic interview Kaufmann Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS)), and executive dysfunction (by Behavior Rating of Executive Function (BRIEF)) were assessed. Results 52.5% of the patients had one or more psychiatric comorbid disorder, and 64.7% had executive dysfunction in a clinically relevant range, with no sex difference in prevalence, while older age was associated with poorer executive function (p=0.013). Having any psychiatric comorbid disorder was associated with poorer executive functions (p=0.001). CSF hypocretin-1 deficiency severity was significantly associated with presence of psychiatric comorbidity (p=0.022) and poorer executive functions (p=0.030), and poorer executive functions was associated with subjective sleepiness (p=0.009). Conclusions The high occurrence of, and association between, psychiatric comorbidity and executive dysfunction underlines the importance of close attention to both these comorbidities in clinical care of NT1.

• Edstorp, Jessica; Wei, Yuxia; Ahlqvist, Emma; Alfredsson, Lars; Grill, Valdemar Erik Robert & Groop, Leif [Show all 12 contributors for this article] (2022). Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults. Diabetologia. ISSN 0012-186X. 66(1), p. 70–81. doi: 10.1007/s00125-022-05763-w. Full text in Research Archive Show summary

  Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA.

• Stenehjem, Jo S.; Støer, Nathalie Charlotte; Ghiasvand, Reza; Grimsrud, Tom Kristian; Babigumira, Ronnie & Rees, Judy R. [Show all 11 contributors for this article] (2022). Prediagnostic serum 25-hydroxyvitamin D and leptin in relation to melanoma-specific death and overall death. Pigment Cell & Melanoma Research. ISSN 1755-1471. 35(2), p. 280–284. doi: 10.1111/pcmr.13026. Full text in Research Archive
• Melsom, Helene Støle; Heiestad, Christina Mathisen; Eftestøl, Einar; Torp, May-Kristin; Gundersen, Kristian & Bjørnebekk, Astrid [Show all 9 contributors for this article] (2022). Reduced arterial elasticity after anabolic–androgenic steroid use in young adult males and mice. Scientific Reports. 12(1). doi: 10.1038/s41598-022-14065-5. Full text in Research Archive Show summary

  Abstract High-doses of anabolic–androgenic steroids (AAS) is efficient for building muscle mass, but pose a risk of cardiovascular side effects. Little is known of the effect of AAS on vasculature, but previous findings suggest unfavorable alterations in vessel walls and vasoreactivity. Here, long-term effect of AAS on vascular function and morphology were examined in male weightlifters, and in a mimicking animal model. Arterial elasticity and morphology were tested with ultrasound, pulse wave velocity (PWV) and carotid intima media thickness (cIMT) in 56 current male AAS users, and 67 non-exposed weightlifting controls (WLC). Female mice were treated with testosterone for 14 days and echocardiography were applied to evaluate vascular function and morphology. Male AAS users had higher PWV (p = 0.044), reduced carotid artery compliance (p = 0.0005), and increased cIMT (p = 0.041) compared to WLC. Similar functional changes were found in the ascending aorta of mice after 7- (p = 0.043) and 14 days (p = 0.001) of testosterone treatment. This animal model can be used to map molecular mechanisms responsible for complications related to AAS misuse. Considering the age-independent stiffening of major arteries and the predictive power of an increase in PWV and cIMT, the long-term users of AAS are at increased risk of severe cardiovascular events.

• Lee-Ødegård, Sindre; Ueland, Thor; Thorsby, Per Medbøe; Aukrust, Pål; Michelsen, Annika Elisabet & Halvorsen, Bente [Show all 8 contributors for this article] (2022). Fetuin-A mediates the difference in adipose tissue insulin resistance between young adult pakistani and norwegian patients with type 2 diabetes. BMC Endocrine Disorders. 22. doi: 10.1186/s12902-022-01127-y. Full text in Research Archive Show summary

  Background South-Asian immigrants to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) and increased adipose tissue insulin resistance (AT-IR), as compared to their Western counterparts. Fetuin-A is a hepatokine known to influence AT-IR. Aim Can plasma fetuin-A concentrations explain an ethnic difference in adipose tissue insulin resistance? Methods We performed a two-step euglycemic-hyperinsulinaemic clamp and measured plasma concentrations of fetuin-A and non-esterified fatty acids (NEFA), in 18 Pakistani and 21 Norwegians with T2DM (age 29–45y) in Norway. AT-IR was calculated as NEFA-suppression during the clamp. The adipokines/cytokines leptin, adiponectin, visfatin, PTX3, IL-1β, INF-γ, and IL-4 were measured in fasting plasma. Liver fat was estimated by CT-scans. Results Despite a lower BMI, Pakistani patients displayed higher AT-IR than Norwegians. NEFA-suppression during clamp was lower in Pakistani than Norwegians (mean=-20.6%, 95%CI=[-40.8, -0.01] and p = 0.046). Plasma fetuin-A concentration was higher in Pakistani than Norwegians (43.4 ng/mL[12.7,74.0], p = 0.007) and correlated negatively to %NEFA-suppression during clamp (rho=-0.39, p = 0.039). Plasma fetuin-A concentration explained 22% of the ethnic difference in NEFA-suppression during the clamp. Pakistani patients exhibited higher plasma leptin and lower PTX3 levels than Norwegian, and plasma visfatin correlated positively to plasma fetuin-A levels in the Pakistani patients. We observed no correlation between plasma fetuin-A and liver fat, but fetuin-A correlated negatively with plasma IL-1β, INF-γ, and IL-4 concentrations. Plasma IL-4 concentration was lower in Pakistani than in Norwegian patients. Conclusion Fetuin-A may contribute to explain the discrepancy in T2DM prevalence between Pakistani and Norwegians patients by influencing AT-IR.

• Pfabigan, Daniela M.; Vezzani, Cecilia; Thorsby, Per Medbøe & Sailer, Uta (2022). Sex difference in human olfactory sensitivity is associated with plasma adiponectin. Hormones and Behavior. ISSN 0018-506X. 145. doi: 10.1016/j.yhbeh.2022.105235. Full text in Research Archive Show summary

  Energy deprivation as well as hormones that regulate appetite and eating can influence olfactory function. This study investigated olfactory sensitivity for a food-related and a non-food odour prior to and after a meal, and its relationship to the energy-regulating hormones ghrelin and adiponectin. The olfactory sensitivity for orange and rose (PEA) odour in healthy, normal-weight volunteers (19 women, 45 men, 1 undisclosed individual) was not affected by the consumption of a meal. Olfactory sensitivity was not associated with concentrations of circulating ghrelin. However, olfactory sensitivity was higher for women than for men, indicating better olfactory performance. This difference between women and men was related to concentrations of plasma adiponectin, an adipose-specific hormone. Adiponectin may thus explain why sex differences in olfactory sensitivity emerge, and may also account for some of the inconsistencies in previous findings on sex differences. Our findings add to the limited literature on the impact of stomach and adipose tissue-derived hormones on olfactory sensitivity. Further studies are needed to establish a causal link between circulating adiponectin and a sex difference in olfactory sensitivity.

• Öberg, Eva Gunnel Johanna; Jorde, Rolf; Figenschau, Yngve Anton; Thorsby, Per Medbøe; Dahl, Sandra Rinne & Winther, Anne [Show all 7 contributors for this article] (2022). Combined hormonal contraceptives and vitamin D metabolism in adolescent girls. Endocrine Connections. 11(3). doi: 10.1530/EC-21-0395. Full text in Research Archive Show summary

  Objective: Combined hormonal contraceptive (CHC) use has been associated with higher total 25-hydroxyvitamin D (25(OH)D) levels. Here, we investigate the relation between CHC use and vitamin D metabolism to elucidate its clinical interpretation. Methods: The cross-sectional Fit Futures 1 included 1038 adolescents. Here, a subgroup of 182 girls with available 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), vitamin D-binding protein (DBP) and measured free 25(OH)D levels, in addition to parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), was investigated. Vitamin D metabolites were compared between girls using (CHC+) and not using CHC (CHC−). Further, the predictability of CHC on 25(OH)D levels was assessed in a multiple regression model including lifestyle factors. The ratios 1,25(OH)2D/25(OH)D and 24,25(OH)2D/25(OH)D (vitamin D metabolite ratio (VMR)) in relation to 25(OH)D were presented in scatterplots. Results: CHC+ (n  = 64; 35% of the girls) had higher 25(OH)D levels (mean ± s.d., 60.3 ± 22.2) nmol/L) than CHC- (n  = 118; 41.8 ± 19.3 nmol/L), P -values <0.01. The differences in 25(OH)D levels between CHC+ and CHC− were attenuated but remained significant after the adjustment of lifestyle factors. CHC+ also had higher levels of 1,25(OH)2D, 24,25(OH)2D, DBP and calcium than CHC−, whereas 1,25(OH)2D/25(OH)D, PTH, FGF23 and albumin were significantly lower. Free 25(OH)D and VMR did not statistically differ, and both ratios appeared similar in relation to 25(OH)D, irrespective of CHC status. Conclusion: This confirms a clinical impact of CHC on vitamin D levels in adolescents. Our observations are likely due to an increased DBP-concentration, whereas the free 25(OH)D appears unaltered.

• Ueland, Grethe Åstrøm; Dahl, Sandra Rinne; Methlie, Paal; Hessen, Saleh; Husebye, Eystein Sverre & Thorsby, Per Medbøe (2022). Adrenal steroid profiling as a diagnostic tool to differentiate polycystic ovary syndrome from nonclassic congenital adrenal hyperplasia: pinpointing easy screening possibilities and normal cutoff levels using liquid chromatography tandem mass spectrometry. Fertility and Sterility. ISSN 0015-0282. 118(2), p. 384–391. doi: 10.1016/j.fertnstert.2022.05.012. Full text in Research Archive Show summary

  Objective: To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff levels and panels of steroid hormones, to improve diagnosis of nonclassic congenital adrenal hyperplasia (NCCAH) and other partial enzyme defects in the adrenals. Design: Prospective cohort analysis. Setting: University hospital-based tertiary endocrine center. Patients: One hundred and twenty-one healthy adults and 65 patients evaluated for possible NCCAH (validation cohort). Interventions: The LC-MS/MS-determined cutoffs for 11 steroids (basal and cosyntropin-stimulated) were defined by 2.5% and 97.5% percentile in healthy subjects. Validation cohort was used for comparison. Main outcome measures: Percentage of patients diagnosed with NCCAH among patients with polycystic ovary syndrome (PCOS)-like symptomatology. Evaluation of the defined LC-MS/MS-based cutoff levels for steroid hormones among this patient group. Results: Of the 65 PCOS-like patients evaluated for possible NCCAH, 8 (12.5%) were discovered and genetically verified, and 2 had classic congenital adrenal hyperplasia. Cosyntropin-stimulated 17-hydroxyprogesterone (17OHP) showed the best diagnostic accuracy for NCCAH with an area under the curve of 0.95 (0.89-1.0 with a sensitivity of 86% and a specificity of 88%. In homozygote patients, 21-deoxycortisol and 17OHP levels were elevated, in heterozygote patients only 17OHP (basal or stimulated) was raised. Four healthy patients in the validation cohort had 17OHP above the basal cutoff. Conclusions: The NCCAH syndrome is frequent in patients with suspected PCOS, and should be considered as a routine screening when assessing infertility. We suggest the use of serum steroid profiling, including 21-deoxycortisol, together with the cosyntropin stimulation test with 17OHP. Our data support a 17OHP cutoff of 8.5 nmol/L (2.8 ng/mL) 60 minutes after cosyntropin stimulation, when measured with LC-MS/MS, significantly lower than current European guidelines. Clinical trials number: NCT0218660. Trial registration: ClinicalTrials.gov NCT00218660. Keywords: NCCAH; Nonclassic congenital adrenal hyperplasia; PCOS; infertility; serum steroid profiling. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

• Trondrud, Liv Monica; Ugland, Cassandra Regine; Ropstad, Erik; Loe, Leif Egil; Albon, Steve & Stien, Audun [Show all 11 contributors for this article] (2022). Stress responses to repeated captures in a wild ungulate. Scientific Reports. 12(1). doi: 10.1038/s41598-022-20270-z. Full text in Research Archive Show summary

  While capture-mark-recapture studies provide essential individual-level data in ecology, repeated captures and handling may impact animal welfare and cause scientifc bias. Evaluating the consequences of invasive methodologies should be an integral part of any study involving capture of live animals. We investigated short- and long-term stress responses to repeated captures within a winter on the physiology, behaviour, and reproductive success of female Svalbard reindeer (Rangifer tarandus platyrhynchus). Short-term responses were evaluated using serum concentrations of glucocorticoids and catecholamines during handling, and post-release recovery times in heart rate and activity levels. Repeated captures were associated with an increase in measured catecholamines and glucocorticoids, except cortisone, and delayed recovery in heart rate but not activity. Four months later, in summer, individuals captured repeatedly in winter exhibited a small increase in behavioural response to human disturbance and had a lower probability of being observed with a calf, compared to animals not captured, or captured only once. Our fndings imply that single annual capture events have no signifcant negative consequences for Svalbard reindeer, but repeated captures within a season may impact ofspring survival in the same year. Such unanticipated side efects highlight the importance of addressing multiple indicators of animal responses to repeated captures

• Kazmi, Syed Sajid Hussain; Safi, Natkai; Berge, Simen Tveten; Kazmi, Marryam; Sundhagen, Jon Otto & Julien, Kari [Show all 10 contributors for this article] (2022). Plasma α-Glutathione S-Transferase in Patients with Chronic Mesenteric Ischemia and Median Arcuate Ligament Syndrome. Vascular Health and Risk Management. ISSN 1176-6344. 18, p. 567–574. doi: 10.2147/VHRM.S365625. Full text in Research Archive Show summary

  Background: Chronic mesenteric ischemia (CMI) due to either atherosclerosis of the mesenteric arteries or median arcuate ligament syndrome (MALS) is an underdiagnosed entity. The etiology of MALS and its existence have been debated and questioned. We aimed to identify plasma biomarkers indicating mesenteric ischemia in patients with CMI and MALS. Methods: Plasma α-glutathione S-transferase (α-GST), intestinal fatty acid-binding protein (I-FABP), citrulline, and ischemia modified albumin (IMA) were analyzed in fifty-eight patients with CMI (Group A, n=44) and MALS (Group B, n=14) before and after revascularization. The plasma levels of these potential biomarkers were compared with those of healthy individuals (Group C, n=16). Group comparison was performed with the Mann–Whitney U-test. Cross-tabulation and its derivatives were obtained. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were calculated. Results: Plasma levels of α-GST were significantly raised in the patients with CMI (7.8 ng/mL, p< 0.001) and MALS (8.4 ng/mL, p< 0.001), as compared with the control Group C (3.3 ng/mL). The threshold for normal median plasma α-GST levels of 4 ng/mL yielded a sensitivity of 93% and 86%, specificity of 86% and 88%, respectively, for the diagnosis of CMI due to atherosclerosis and MALS. AUC of ROC curves was 0.96 (p< 0.0001) for CMI and 0.85 (p< 0.002) for MALS. The patient groups did not differ from the healthy controls in any other biomarkers. Conclusion: Plasma α-GST levels are elevated in CMI and MALS patients. Elevated plasma levels of α-GST suggest ischemia as the etiology of MALS.

• Molteberg, Ellen; Taubøll, Erik; Kverneland, Magnhild; Iversen, Per Ole; Selmer, Kaja Kristine & Nakken, Karl Otto [Show all 8 contributors for this article] (2022). Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet. Epilepsia. ISSN 0013-9580. 63(4), p. 880–891. doi: 10.1111/epi.17169. Full text in Research Archive Show summary

  Abstract Objective The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism. Methods Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin. Results After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (≥25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant. Significance Twelve weeks of MAD treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

• Pfabigan, Daniela Melitta; Frogner, Erik Rimestad; Erik, Schéle; Thorsby, Per Medbøe; Skålhegg, Bjørn Steen & Dickson, Suzanne L. [Show all 7 contributors for this article] (2022). The “hunger” hormone ghrelin is associated with neural activation during touch, but not its affective experience. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.05.10.491384. Full text in Research Archive
• Bjørnebekk, Astrid; Scarth, Morgan; Neupane, Sudan Prasad; Westlye, Lars Tjelta; Hullstein, Ingunn Riise & Thorsby, Per Medbøe [Show all 7 contributors for this article] (2022). Use of high-dose androgens is associated with reduced brain derived neurotrophic factor in male weightlifters. Neuroendocrinology. ISSN 0028-3835. 113(1), p. 36–47. doi: 10.1159/000526418. Full text in Research Archive Show summary

  Introduction: Use of high-dose androgens causes drastic changes in hormonal milieu and is associated with adverse medical, psychological, and cognitive effects. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors plays a critical role in neuroplasticity, with implications for cognitive function and mental health. The impact of long-term, high-dose androgen use on BDNF in a natural setting has not been investigated. This study examined the association between long-term androgen exposure and BDNF levels, and the links between BDNF, heavy resistance exercise, hormones, androgens and mental health. Methods: We measured serum levels of BDNF and sex steroid hormones in male weightlifters (N=141) with a history of current (n=59), past (n=29) or no (n=52) androgen use. All participants completed questionnaires assessing maximum strength and measures of anxiety and depression. Group differences in BDNF were tested using general linear models adjusting for age, and associations between BDNF and strength, anxiety and depression using Pearson’s or Kendall’s correlations. Results: Both current (mean: 44.1 ng/ml (SD:12.7)) and past (39.5 ng/ml (SD:13.9)) androgen users showed lower serum BDNF levels compared to non-using controls (51.5 (SD: 15.3), p&lt;.001, ηp²=0.10). BDNF levels were negatively related to maximal strength, and with hormonal status in past androgen users, but no significant associations were found with measures of depression and anxiety. Conclusion: Lower circulating BDNF concentrations in current and past androgen users, suggest that high-dose androgen exposure triggers persistent changes in BDNF expression. Further studies are needed to verify the relationship and its’ potential clinical implications.

• Syversen, Unni; Mosti, Mats Peder; Mynarek, Ida Maria; Vedal, Trude Seselie Jahr; Aasarød, Kristin Matre & Basso, Trude [Show all 11 contributors for this article] (2021). Evidence of impaired bone quality in men with type 1 diabetes: A cross-sectional study. Endocrine Connections. 10(8), p. 955–964. doi: 10.1530/EC-21-0193. Full text in Research Archive Show summary

  Objective Type 1 diabetes (T1D) is associated with substantial fracture risk. Bone mineral density (BMD) is, however, only modestly reduced, suggesting impaired bone microarchitecture and/or bone material properties. Yet, the skeletal abnormalities have not been uncovered. Men with T1D seem to experience a more pronounced bone loss than their female counterparts. Hence, we aimed to examine different aspects of bone quality in men with T1D. Design and Methods In this cross-sectional study, men with T1D and healthy male controls were enrolled. BMD (femoral neck, total hip, lumbar spine, whole body) and spine trabecular bone score (TBS) were measured by dual x-ray absorptiometry, and bone material strength index (BMSi) was measured by in vivo impact microindentation. HbA1c and bone turnover markers were analyzed. Results Altogether, 33 men with T1D (43 ± 12 years) and 28 healthy male controls (42 ± 12 years) were included. Subjects with T1D exhibited lower whole-body BMD than controls (P = 0.04). TBS and BMSi were attenuated in men with T1D vs controls (P = 0.016 and P = 0.004, respectively), and T1D subjects also had a lower bone turnover. The bone parameters did not differ between subjects with or without diabetic complications. Duration of disease correlated negatively with femoral neck BMD but not with TBS or BMSi. Conclusions This study revealed compromised bone material strength and microarchitecture in men with T1D. Moreover, our data confirm previous studies which found a modest decrease in BMD and low bone turnover in subjects with T1D. Accordingly, bone should be recognized as a target of diabetic complications.

• Dahll, Louise J. Koren; Haave, Ellen Marie; Dahl, Sandra Rinne; Aas, Finn Erik & Thorsby, Per Medbøe (2021). Endogenous anti-streptavidin antibodies causing erroneous laboratory results more common than anticipated. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 81(2), p. 92–103. doi: 10.1080/00365513.2020.1858493. Full text in Research Archive Show summary

  All immunological methods are vulnerable to different kinds of interference. The purpose of this work was to study the cause and frequency of method-dependent interference in the Roche thyroid immunoassays. Serum samples with discordant thyroid function tests (TFT) were selected from samples sent to the Hormone Laboratory, Oslo University Hospital from June 2013 to September 2018. We identified 93 patients with discordant pathological TFT when analysed with the Roche methods and normal results when analysed with alternative methods. 42 of these samples were sent to Roche Diagnostics (Germany) for investigation of the interfering substance. Roche found interference to be caused by the presence of endogenous anti-streptavidin antibodies (ASA) (34 of 42 patients), ruthenium or the idiotype of the ruthenium labelled antibody (3 of 42 patients) and mouse antigens (1 of 42 patients). Method-dependent interference was estimated to affect 0.37% of the patients investigated in our laboratory. Interference due to the presence of endogenous ASA were further explored in other (non-thyroid) immunoassays by comparing analyte levels before and after pre-adsorption of the patients’ sera with streptavidin-coated paramagnetic beads. An underestimation of hormone levels was observed in sandwich immunoassays, while an overestimation was found in competitive assays. Method-dependent interference in Roche thyroid immunoassays is caused mainly by ASA and is not a very rare phenomenon. Misleading results may lead to misdiagnosis and inappropriate medical treatment. The supplier of the assay should be alerted when the available alternative methodology reveals method-dependent errors.

• Solevåg, Anne Lee; Zykova, Svetlana; Thorsby, Per Medbøe & Schmölzer, Georg M. (2021). Metabolomics to diagnose oxidative stress in perinatal asphyxia: Towards a non-invasive approach. Antioxidants. 10(11), p. 1–11. doi: 10.3390/antiox10111753. Full text in Research Archive
• Oftedal, Aurora; Bekkhus, Mona; Haugen, Guttorm Nils; Braithwaite, Elizabeth; Bollerslev, Jens & Godang, Kristin [Show all 8 contributors for this article] (2021). Changes in maternal cortisol, cortisol binding globulin and cortisone levels following diagnosis of fetal anomaly. Psychoneuroendocrinology. ISSN 0306-4530. 135. doi: 10.1016/j.psyneuen.2021.105574. Full text in Research Archive Show summary

  The diagnosis of fetal anomaly can be a major stressor to the expectant mother. Current understanding of the relationship between psychological stress and cortisol in pregnancy is limited. This study examined: (1) differences in the ratio of serum cortisol to cortisol binding globulin (SC/CBG) and cortisone levels among women with and without a diagnosis of fetal anomaly, (2) the association between self-reported stress and cortisol from mid to late pregnancy, and (3) the agreement between two different techniques for analyzing cortisol: liquid chromatography-tandem mass spectrometry (LC-MS/MS) and radioimmunoassay (RIA). Thirty-six pregnant women with a diagnosis of fetal anomaly (study group) and 101 women with healthy pregnancies (comparison group) provided blood samples and completed self-report questionnaires at gestational weeks 18–24 (T1) and 30 (T2). In the comparison group, mean SC/CBG increased from 0.341 nmol/L at T1 to 0.415 at T2 (p < .001), whereas in the study group there was no change (0.342 nmol/L at T1, 0.343 at T2). There was no difference in cortisone levels between the groups at either timepoints. There was a negative association between both depression and traumatic stress at T1, and SC/CBG at T2 (p < .05). There was no association between general distress and SC/CBG. The two methods for analyzing cortisol gave similar results, but with LC-MS/MS showing a lower detection limit than RIA. Increased cortisol with advancing gestational age is expected, thus these findings indicate that under certain conditions of severe stress there may be a suppression of maternal cortisol increase from mid to late gestation. The discrepancy does not seem to be due to differences in the metabolization of cortisol, as indicated by the similar levels of cortisone. Further research is needed in order to understand the potential underlying mechanisms limiting the expression of cortisol in response to certain types of stress in pregnancy.

• Viste, Rannveig; Viken, Marte Kathrine; Lie, Benedicte Alexandra; Juvodden, Hilde Therese; Nordstrand, Sebjørg E. H. & Thorsby, Per M. [Show all 9 contributors for this article] (2021). High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y<inf>11</inf>protein levels in narcolepsy type 1. Sleep. ISSN 0161-8105. 44(8), p. 1–12. doi: 10.1093/sleep/zsab062. Full text in Research Archive Show summary

  Abstract Study Objectives Narcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls. Methods The P2RY11 SNP was genotyped in 100 patients (90/100 H1N1-(Pandemrix)-vaccinated), 119 related and 123 non-related controls. CD4 and CD8 T lymphocyte P2Y11 protein levels were quantified using flow cytometry in 167 patients and relatives. Symptoms and sleep recording parameters were also collected. Results We found an association between NT1 and the rs2305795 A allele (OR = 2, 95% CI (1.3, 3.0), p = 0.001). T lymphocyte P2Y11 protein levels were significantly lower in patients and relatives homozygous for the rs2305795 risk A allele (CD4: p = 0.012; CD8: p = 0.007). The nocturnal sleep fragmentation index was significantly negatively correlated with patients’ P2Y11 protein levels (CD4: p = 0.004; CD8: p = 0.006). Mean MSLT sleep latency, REM-sleep latency, and core clinical symptoms were not associated with P2Y11 protein levels. Conclusions We confirmed that the P2RY11 polymorphism rs2305795 is associated with NT1 also in a mainly H1N1-(Pandemrix)-vaccinated cohort. We demonstrated that homozygosity for the A risk allele is associated with lower P2Y11 protein levels. A high level of nocturnal sleep fragmentation was associated with low P2Y11 levels in patients. This suggests that P2Y11 has a previously unknown function in sleep-wake stabilization that affects the severity of NT1.

• Birkeland, Eline; Gharagozlian, Sedegheh; Birkeland, Kåre I.; Holm, Oda Kristine S.; Thorsby, Per Medbøe & Aas, Anne-Marie (2021). Effect of inulin-type fructans on appetite in patients with type 2 diabetes: A randomised controlled crossover trial. Journal of Nutritional Science (JNS). 10, p. 1–11. doi: 10.1017/jns.2021.70. Full text in Research Archive Show summary

  Abstract The aim of the study was to investigate the effect of prebiotic fibres on appetite-regulating hormones, subjective feeling of appetite and energy intake in subjects with type 2 diabetes. Data presented are secondary outcomes of a study investigating the effect of prebiotics on glucagon-like peptide-1 and glycaemic regulation. We conducted a randomised and placebo-controlled crossover trial to evaluate the effects of 16 g/d of inulin-type fructans or a control supplement (maltodextrin) for 6 weeks in randomised order, with a 4-week washout period in-between, on appetite in thirty-five men and women with type 2 diabetes. Data were collected at visits before and after each treatment: plasma concentration of the satiety-related peptides ghrelin and peptide YY (PYY) were assessed during a standardised mixed meal. The subjective sensation of appetite was evaluated in response to an ad libitum lunch by rating the visual analogue scale. Twenty-nine individuals (twelve women) were included in the analyses. Compared to control treatment, the prebiotics did not affect ghrelin ( P =0⋅71) or the ratings of hunger ( P = 0⋅62), satiety ( P = 0⋅56), fullness ( P = 0⋅73) or prospective food consumption ( P = 0⋅98). Energy intake also did not differ between the treatments. However, the response of PYY increased significantly after the control treatment with mean ( sem ) 11⋅1 (4⋅3) pg/ml when compared to the prebiotics −0⋅3 (4⋅3) pg/ml ( P = 0⋅013). We observed no effect of inulin-type fructans on appetite hormones, subjective feeling of appetite or energy intake in patients with type 2 diabetes.

• Bornstedt, Mette Eskild; Gjerlaugsen, Nina; Olstad, Ole Kristoffer; Berg, Jens Petter; Bredahl, May K. Lyamouri & Thorsby, Per Medbøe (2020). Vitamin D metabolites influence expression of genes concerning cellular viability and function in insulin producing β-cells (INS1E). Gene. ISSN 0378-1119. 746:144649, p. 1–8. doi: 10.1016/j.gene.2020.144649. Full text in Research Archive Show summary

  Background Studies have shown that vitamin D can enhance glucose-stimulated insulin secretion (GSIS) and change the expression of genes in pancreatic β-cells. Still the mechanisms linking vitamin D and GSIS are unknown. Material and methods We used an established β-cell line, INS1E. INS1E cells were pre-treated with 10 nM 1,25(OH)2vitamin D or 10 nM 25(OH)vitamin D for 72 h and stimulated with 22 mM glucose for 60 min. RNA was extracted for gene expression analysis. Results Expression of genes affecting viability, apoptosis and GSIS changed after pre-treatment with both 1,25(OH)2vitamin D and 25(OH)vitamin D in INS1E cells. Stimulation with glucose after pre-treatment of INS1E cells with 1,25(OH)2vitamin D resulted in 181 differentially expressed genes, whereas 526 genes were differentially expressed after pre-treatment with 25(OH)vitamin D. Conclusion Vitamin D metabolites may affect pancreatic β-cells and GSIS through changed gene expression for genes involved in β-cell function and viability.

• Ingstad, Frida; Solberg, Lene Bergendal; Nordsletten, Lars; Thorsby, Per Medbøe; Hestnes, Ingvild & Frihagen, Frede Jon (2020). Vitamin D status and complications, readmissions, and mortality after hip fracture. Osteoporosis International. ISSN 0937-941X. doi: 10.1007/s00198-020-05739-9. Full text in Research Archive Show summary

  Summary Low vitamin D in patients with hip fracture is common. In the present study, 407 of 872 (47%) patients had serum calcidiol less than 50 nmol/L. Patients with low vitamin D had more delirium, more new hip fractures, and more medical readmissions, but not more orthopedic complications after 1 year. Introduction We wanted to study the relation between vitamin D level and postoperative orthopedic and medical complications in patients with hip fracture. In addition, we investigated the effect of giving a single-dose cholecalciferol 100.000 IU. Methods Data were taken from the local hip fracture register. Logistic regression analyses including vitamin D level and potentially confounding variables were performed for complications and readmissions. Results A total of 407 (47%) of 872 included hip fractures had low vitamin D at baseline. A total of 155 (18%) developed delirium, and the risk was higher in vitamin D-deficient patients (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.04 to 2.12; p = 0.03). A total of 261 (30%) were readmitted for non-hip-related conditions. Low vitamin D was associated with a higher risk of medical readmissions within 30 days (OR 1.64 (1.03 to 2.61); p = 0.036) and 12 weeks (OR 1.47 (95% CI 1.02 to 2.12); p = 0.039). There was a higher risk of a new hip fracture (OR 2.84 (95% CI 1.15 to 7.03) p = 0.024) in vitamin D-deficient patients. A total of 105 (12%) developed at least one orthopedic complication, with no correlation to baseline vitamin D. Among vitamin D-deficient patients, those receiving a single-dose of 100.000 IU cholecalciferol had fewer orthopedic complications (OR 0.32 (95% CI 0.11 to 0.97) p = 0.044) the first 30 days after surgery. Conclusion Low vitamin D at admission for hip fracture increased the risk of delirium, a new hip fracture, and medical readmissions, but not orthopedic complications. The role of vitamin D supplementation to prevent orthopedic complications requires further study.

• Nordstrand, Sebjørg Elizabeth Hesla; Juvodden, Hilde Therese; Viste, Rannveig; Rootwelt-Revheim, Terje; Karlsen, Tor-Ivar & Thorsby, Per Medbøe [Show all 10 contributors for this article] (2020). Obesity and other medical comorbidities among NT1 patients after the Norwegian H1N1 influenza epidemic and vaccination campaign. Sleep. ISSN 0161-8105. 43(5). doi: 10.1093/sleep/zsz277. Full text in Research Archive
• Stenehjem, Jo S.; Støer, Nathalie Charlotte; Ghiasvand, Reza; Grimsrud, Tom Kristian; Babigumira, Ronnie & Rees, Judy R. [Show all 11 contributors for this article] (2020). Prediagnostic serum 25-hydroxyvitamin D and melanoma risk. Scientific Reports. 10, p. 1–11. doi: 10.1038/s41598-020-77155-2. Full text in Research Archive Show summary

  Abstract Previous studies of serum 25-hydroxyvitamin D (25(OH)D) in relation to melanoma have shown conflicting results. We conducted a nested case–control study of 708 cases and 708 controls, using prediagnostically collected serum, to study 25(OH)D and melanoma risk in the population-based Janus Serum Bank Cohort. Stratified Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for ultraviolet radiation (UVR) indicators and stratified by ambient UVB of residence and body mass index (BMI). Non-linear associations were studied by restricted cubic splines. Missing data were handled with multiple imputation by chained equations. We found an HR of melanoma risk of 1.01 (95% CI: 0.99, 1.04) and an HR imputed of 1.02 (95% CI: 1.00, 1.04) per 5-nmol/L increase. The spline model showed exposure-risk curves with significantly reduced melanoma risk between 60 and 85 nmol/L 25(OH)D (reference 50 nmol/L). Non-significant J-shaped curves were found in sub-analyses of subjects with high ambient UVB of residence and of subjects with BMI &lt; 25 kg/m 2 . Our data did not yield persuasive evidence for an association between 25(OH)D and melanoma risk overall. Serum levels within the medium range might be associated with reduced risk, an association possibly mediated by BMI.

• Hansen, Berit M Hjelde; Juvodden, Hilde Therese; Nordstrand, Sebjørg Elizabeth Hesla; Viste, Rannveig; Thorsby, Per Medbøe & Swanson, David [Show all 9 contributors for this article] (2020). High prevalence of ADHD symptoms in unmedicated youths with post-H1N1 narcolepsy type 1. Sleep Medicine. ISSN 1389-9457. 75, p. 171–180. doi: 10.1016/j.sleep.2020.06.014. Full text in Research Archive Show summary

  Objectives To characterize attention deficit-hyperactivity disorder (ADHD) symptoms in unmedicated post-H1N1 narcolepsy type 1 (NT1) youths, and explore associations between ADHD symptoms and the narcolepsy phenotype. Methods A total of 50 consecutively enrolled post-H1N1 NT1 youths (7–20 years, 62% females, 98% HLA-DQB1∗06:02-positive, 98% CSF hypocretin-1 deficient, 88% vaccinated) were assessed after two weeks off medication for ADHD (ADHD diagnosis pre/post-narcolepsy, parent-rated ADHD symptoms) and narcolepsy-phenotyped (semi-structured interview, Stanford Sleep Questionnaire, Epworth Sleepiness Scale, polysomnography (PSG), Multiple Sleep Latency Test (MSLT)). Results In sum, 26 (52%) and 15 (30%) of participants had ADHD symptoms above and below the clinical significant cut-off, respectively, while 9 (18%) had no ADHD symptoms. High values were found for ADHD total score (mean (SD), 17.9 (9.5)) and ADHD subscores (inattentive score, 11.0 (6.3); hyperactive/impulsivity score, 6.9 (4.7)). These were significantly higher than previously reported in a mainly medicated narcolepsy cohort (p < 0.0001). Age, gender and disease duration did not influence scores. Two participants (4%) had ADHD diagnosis prior to narcolepsy onset. ADHD symptoms were correlated with parent-rated, but not with patient rated ESS scores, objective sleepiness (mean sleep latency), sleep fragmentation (sleep stage shift index, awakening index), or CSF hypocretin-1 level. Conclusion Comorbid ADHD symptoms were more prevalent in unmedicated post-H1N1 NT1 youths than previously reported in mainly medicated pediatric narcolepsy cohorts. The high prevalence was not due to pre-existing ADHD and generally not correlated with core narcolepsy sleep/wake phenotype characteristics, indicating that the ADHD symptoms were not a direct consequence of disturbed sleep or daytime sleepiness.

• Juvodden, Hilde Therese; Viken, Marte Kathrine; Nordstrand, Sebjørg Elizabeth Hesla; Viste, Rannveig; Westlye, Lars Tjelta & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2020). HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives. Sleep. ISSN 0161-8105. 43(3), p. 1–11. doi: 10.1093/sleep/zsz239. Full text in Research Archive Show summary

  Abstract Study Objectives To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives. Methods Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semistructured interviews, Stanford Sleep Questionnaire, polysomnography, and multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls). A subsample (74 patients, 114 relatives) was investigated for associations between HLA-loci and continuous sleep variables using logistic regression. Identified candidate HLA-loci were explored for HLA allele associations with hypnagogic hallucinations and sleep paralysis in 90 patients, and patient allele findings were checked for similar associations in 202 relatives. Results DQB1*06:02 heterozygous post-H1N1 NT1 patients (84.4% H1N1-vaccinated) showed several significant HLA associations similar to those reported previously in samples of mainly sporadic NT1, i.e. DQB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:07, DRB1*11:04, A*25:01, B*35:03, and B*51:01, and novel associations, i.e. B*14:02, C*01:02, and C*07:01. Parents HLA alleles did not deviate significantly from controls. The HLA-C locus was associated with sleep parameters in patients and relatives. In patients C*02:02 seems to be associated with protective effects against sleep paralysis and hypnagogic hallucinations. Conclusions Our findings of similar risk/protective HLA-alleles in post-H1N1 as in previous studies of mainly sporadic narcolepsy support similar disease mechanisms. We also report novel allelic associations. Associations between HLA-C and sleep parameters were seen independent of NT1 diagnosis, supporting involvement of HLA-C in sleep subphenotypes.

• Kvammen, Janne Anita; Thomassen, Rut Anne; Kjeserud, Christina; Sæland, Camilla; Godang, Kristin & Bollerslev, Jens [Show all 10 contributors for this article] (2020). Bone mineral density and vitamin D in paediatric intestinal failure patients receiving home parenteral nutrition. Clinical Nutrition ESPEN. ISSN 2405-4577. 39, p. 234–241. doi: 10.1016/j.clnesp.2020.06.006. Full text in Research Archive Show summary

  Background & aims Patients with intestinal failure (IF) are dependent on long-term home parenteral nutrition (HPN) to ensure growth and development. The primary aim of the present study was to assess bone mineral density (BMD) and vitamin D status in paediatric IF patients on HPN and a group of healthy children aged 2–18 years. Secondary aims were to assess growth, body composition, nutrient provision and physical activity. Methods An observational cross-sectional study was performed at Oslo University Hospital and at the Department of Nutrition, University of Oslo, from January to September 2017. Dual energy x-ray absorptiometry (DXA; Lunar Prodigy in IF patients and Lunar iDXA in healthy subjects) was performed to assess BMD and body composition. BMD z-score (BMDz) was calculated for total body and lumbar spine L2-L4 based on the integrated reference population in the software. Weight and height were measured for growth assessment. Nutrient provision was assessed by a 4-day food record. Blood samples were analysed for 25-hydroxy-vitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D). Physical activity was reported by a questionnaire. Results Nineteen IF patients and 50 healthy children were included. The mean age of participants was 10.0 years. The aetiology of IF patients was paediatric intestinal pseudo-obstruction (58%), short bowel syndrome (26%), and intestinal enteropathy (16%). Lower median BMDz for total body (−0.4 vs 1.1, P < 0.001) and lumbar spine L2-L4 (−0.9 vs 0.2, P = 0.01) were found in the IF group compared with the healthy children. Vitamin D provision was significantly higher in IF patients (17 μg/d vs 5.3 μg/d, P < 0.001). Both groups were sufficient in 25(OH)D (IF patients 71 nmol/L vs healthy 81 nmol/L). Nevertheless, IF patients had significantly lower 1,25(OH)2D than healthy children (71 pmol/L vs 138 pmol/L, P < 0.001). The IF group was significantly shorter (height for age z-score −1,5 vs 0,1, P = 0.001) and lighter (weight for age z-score −1,0 vs 0,1, P = 0.009) compared with the healthy subjects. BMIz did not differ; however, body fat percentage was significantly higher in IF patients compared with healthy children (34% vs 25%, P = 0.02). A lower frequency of physical activity was found in the IF group compared with the healthy group (P = 0.001). Conclusions Paediatric IF patients on HPN had lower BMD, impaired growth, and higher body fat percentage in comparison with the healthy children. Despite a higher total supply of vitamin D in the IF group, the levels of 25(OH)D did not differ. Nevertheless, a significantly lower level of 1,25(OH)2D was found in IF patients. The results raise questions regarding differences between oral and parenteral vitamin D provision and whether intestinal function is important for the metabolism of vitamin D.

• Molteberg, Ellen; Thorsby, Per Medbøe; Kverneland, Magnhild; Iversen, Per Ole; Selmer, Kaja Kristine & Nakken, Karl Otto [Show all 7 contributors for this article] (2020). Effects of modified Atkins diet on thyroid function in adult patients with pharmacoresistant epilepsy. Epilepsy & Behavior. ISSN 1525-5050. 111:107285. doi: 10.1016/j.yebeh.2020.107285. Full text in Research Archive Show summary

  Introduction The use of ketogenic diet as a supplement to antiseizure medication (ASM) in refractory epilepsy has increased the past decades. This high-fat, low-carbohydrate diet mimics the metabolic state of fasting and is generally well-tolerated. However, the long-term adverse effects of the diet are unclear. The purpose of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, may have an impact on thyroid hormone levels. Methods We assessed thyroid function by measuring thyroid stimulation hormone (TSH), fT4, T3, fT3, and rT3 before diet start (baseline) and after 12 weeks on the diet in 53 adult patients with drug-resistant epilepsy. Further, we examined the correlation between the changes in thyroid function during dietary treatment and type of (i) change in seizure frequency, (ii) drugs in use, and (iii) degree of ketosis. Results After 12 weeks on the diet, we found a significant reduction in T3 and fT3 values (13.4% and 10.6%, respectively) and a significant increase in fT4 values (12.1%) compared with baseline. In addition, there was an insignificant increase in TSH and rT3. These changes were similar in women and men, and there was no correlation to drugs in use (enzyme-inducing vs. nonenzyme-inducing drugs), changes in seizure frequency, or level of ketosis. Conclusion This study indicates that dietary treatment for epilepsy may bring about a modest fall in thyroid hormone levels. This could be relevant for those patients with low thyroid hormones and those treated with ASMs known to lower thyroid hormone levels. A cumulative effect of ASMs, low basal thyroid hormone levels, and ketogenic diet may therefore be of clinical importance in the case of thyroid hormones when treating patients with MAD.

• Bornstedt, Mette Eskild; Gjerlaugsen, Nina; Pepaj, Milaim; Bredahl, May K. Lyamouri & Thorsby, Per Medbøe (2019). Vitamin D increases glucose stimulated insulin secretion from insulin producing beta cells (INS1E). International Journal of Endocrinology and Metabolism (IJEM). ISSN 1726-913X. 17:e74255(1), p. 1–5. doi: 10.5812/ijem.74255. Full text in Research Archive
• Panton, Kristine Kollerøs; Mikkelsen, Gustav; Irgens, Wenche Elna Øiestad; Hovde, Ann Kristin; Killingmo, Marte Wien & Øien, Monja Airin [Show all 8 contributors for this article] (2019). New reference intervals for cortisol, cortisol binding globulin and free cortisol index in women using ethinyl estradiol. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 79(5), p. 314–319. doi: 10.1080/00365513.2019.1622031. Full text in Research Archive Show summary

  Healthy women using contraceptives containing a low dose of an estrogen may have a higher serum concentration of cortisol (s-cortisol) and cortisol binding globulin (s-CBG) than the commonly used upper reference limits. There are no published reference intervals for s-cortisol, s-CBG, serum free cortisol index (s-FCI) or cortisol in saliva (sa-cortisol) for these women. The aim was to establish the above-mentioned reference intervals and document the differences in s-cortisol and s-CBG in one group of women using and another group not using ethinyl estradiol (EE). In this cross-sectional study, the reference limits presented were given as the 2.5 and 97.5 percentiles of the distribution of reference values in a population of 277 healthy volunteer women, aged 18–45 years. 157 women were not using any type of estrogen, while 120 women were using contraceptives containing a daily dose of 15–35 μg of EE. Serum and salivary cortisol, and serum CBG were measured using standard laboratory methods. S-FCI was calculated as s-cortisol/s-CBG. The reference intervals for s-cortisol in samples collected at 0800–1030 am in women using and not using EE contraception were: 284–994 nmol/L and 159–569 nmol/L respectively, and for s-CBG: 847–3366 nmol/L and 860–1940 nmol/L, respectively. For s-FCI and sa-cortisol, no clinically significant differences were found. Sa-cortisol may be the preferred measurand for evaluation of possible hypercortisolism in women using estrogens, since cortisol in saliva is not influenced by estrogen. If assessing morning s-cortisol and s-CBG in women using EE, we recommend using separate – and not the commonly used – reference intervals.

• Jorde, Rolf; Stunes, Astrid Kamilla; Kubiak, Julia Magdalena; Joakimsen, Ragnar Martin; Grimnes, Guri & Thorsby, Per Medbøe [Show all 7 contributors for this article] (2019). Effects of vitamin D supplementation on bone turnover markers and other bone-related substances in subjects with vitamin D deficiency. Bone. ISSN 8756-3282. 124, p. 7–13. doi: 10.1016/j.bone.2019.04.002. Full text in Research Archive Show summary

  In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D3 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P < 0.01). No significant effects were seen on serum carboxyl-terminal telopeptide of type 1 collagen (CTX-1), Dickkopf-1, sclerostin, tumor necrosis factor-alpha, osteoprotegerin, receptor activator of nuclear factor ĸB ligand, or leptin. Subgroup analyses on subjects with low baseline serum 25(OH)D did not yield additional, significant results. In subjects with high baseline serum parathyroid hormone (PTH) > 6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects.

• Balasuriya, Chandima Nirupa Dilruks; Larose, Tricia L; Mosti, Mats Peder; Evensen, Kari Anne Indredavik; Jacobsen, Geir Wenberg & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2019). Maternal serum retinol, 25(OH)D and 1,25(OH)2D concentrations during pregnancy and peak bone mass and trabecular bone score in adult offspring at 26-year follow-up. PLOS ONE. 14:e0222712(9), p. 1–15. doi: 10.1371/journal.pone.0222712. Full text in Research Archive Show summary

  Background Vitamin A and D deficiency is prevalent in pregnant women worldwide. Both vitamins are involved in fetal skeletal development. A positive association between maternal vitamin D levels and offspring bone mineral density (BMD) at adulthood has been observed. The impact of maternal vitamin A status in pregnancy on offspring peak bone mass remains unclear. Method and findings Forty-one mother-child pairs were recruited from a population-based prospective cohort study in Trondheim, Norway, where pregnant women were followed from gestational week 17. Their term-born infants were followed from birth (1986–88). Regression analyses were performed for vitamin A (retinol), 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in maternal serum (gestational weeks 17, 33, 37) and cord blood. Offspring BMD and spine trabecular bone score (TBS), a measure of bone quality, were analyzed by dual x-ray absorptiometry at 26 years. Average levels during pregnancy of retinol, 25(OH)D and 1,25(OH)2D were 1.66 (0.32) μmol/L, 59.0 (20.6) nmol/L, and 251.3 (62.4) pmol/L, respectively. 1,25(OH)2D levels were similar in those with 25(OH)D levels <30 and >75 nmol/L. After adjustment for maternal age, BMI, smoking, and education, and offspring birth weight, maternal serum retinol was positively associated with offspring spine BMD [mean change 30.8 (CI 7.6, 54.0) mg/cm2 per 0.2 μmol/L retinol], and with offspring TBS, although non-significant (p = 0.08). No associations were found between maternal 25(OH)D and 1,25(OH)2D levels and offspring bone parameters. Vitamin levels in cord blood were not associated with offspring BMD or TBS. Conclusions This is the first study to show an association between maternal vitamin A status and offspring peak bone mass. Our findings may imply increase future risk for osteoporotic fracture in offspring of mothers with suboptimal vitamin A level. No associations were observed between 25(OH)D and 1,25(OH)2D and offspring BMD.

• Jorde, Rolf; Stunes, Astrid Kamilla; Kubiak, Julia Magdalena; Grimnes, Guri; Thorsby, Per Medbøe & Syversen, Unni (2019). Smoking and other determinants of bone turnover. PLOS ONE. 14:e0225539(11), p. 1–16. doi: 10.1371/journal.pone.0225539. Full text in Research Archive Show summary

  The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman’s rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.

• Svanevik, Marius; Risstad, Hilde; Hofsø, Dag; Høgestøl, Ingvild Kristine; Kristinsson, Jon Adalsteinn & Sandbu, Rune [Show all 10 contributors for this article] (2019). Bone Turnover Markers After Standard and Distal Roux-en-Y Gastric Bypass: Results from a Randomized Controlled Trial. Obesity Surgery. ISSN 0960-8923. 29(9), p. 2886–2895. doi: 10.1007/s11695-019-03909-1. Full text in Research Archive Show summary

  Background: Roux-en-Y gastric bypass is associated with increased risk of bone fractures. Malabsorptive procedures may be associated with secondary hyperparathyroidism and detrimental effects on bone health. We aimed to compare the effects of standard and distal gastric bypass on bone turnover markers 2 years after surgery. Methods: Patients with body mass index (BMI) 50–60kg/m2 (n=113) were randomized to standard or distal gastric bypass,105 patients (95%) completed 2-year follow-up. Serum C-terminal telopeptide of type I collagen (CTX-1), procollagen type I Npropeptide (PINP), and bone-derived alkaline phosphatase (BALP) was measured at baseline and up to 2 years after surgery. ANCOVA and linear mixed models were used to compare groups. Results: The levels of bone turnover markers increased significantly in both groups, with no statistically significant difference betweengroups.Two years after standard and distal gastric bypass mean (SD) CTX-1 were 0.81 (0.32) and 0.83 (0.31) μg/L (p= 0.38), mean PINP was 77.6 (23.2) and 77.7 (29.3) μg/L (p=0.42), and BALP 47.9 (21.9) vs. 50.7 (19.6) μg/L (p=0.38), respectively. Multiple linear regression analyses showed that PINP and BALP correlated positively (p=0.01 and p <0.001) with PTH, but only BALP was significantly higher in patients with secondary hyperparathyroidism (p=0.001). Type of surgery, vitamin D serum concentrations, and 2-year BMI were all independently associated with PTH levels. Conclusion: A comparable increase in bone turnover markers 2 years after standard and distal gastric bypass was observed. There was a higher prevalence of secondary hyperparathyroidism after distal gastric bypass, but this did not impact bone turnover markers.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Dietrichs, Espen; Thorsby, Per Medbøe & Westlye, Lars Tjelta [Show all 7 contributors for this article] (2019). Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing. Sleep. ISSN 0161-8105. 42:zsz082(7), p. 1–12. doi: 10.1093/sleep/zsz082. Full text in Research Archive Show summary

  Study Objectives To assess brain activation patterns in response to fun-rated and neutral-rated movies we performed functional magnetic resonance imaging (fMRI) during a humor-paradigm in narcolepsy type 1 (NT1) patients with cataplexy (muscle atonia triggered by emotions) and controls. The fMRI-humor-paradigm consisted of short movies (25/30 with a humorous punchline; 5/30 without a humorous punchline [but with similar build-up/anticipation]) rated by participants based on their humor experience. We included 41 NT1 patients and 44 controls. Group-level inferences were made using permutation testing. Permutation testing revealed no group differences in average movie ratings. fMRI analysis found no group differences in brain activations to fun-rated movies. Patients showed significantly higher activations compared to controls during neutral-rated movies; including bilaterally in the thalamus, pallidum, putamen, amygdala, hippocampus, middle temporal gyrus, cerebellum, brainstem and in the left precuneus, supramarginal gyrus, and caudate. We found no brain overactivation for patients during movies without a humorous punchline (89.0% neutral-rated). Group analyses revealed significantly stronger differentiation between fun-rated and neutral-rated movies in controls compared with patients (patients showed no significant differentiation), including bilaterally in the inferior frontal gyrus, thalamus, putamen, precentral gyrus, lingual gyrus, supramarginal gyrus, occipital areas, temporal areas, cerebellum and in the right hippocampus, postcentral gyrus, pallidum, and insula. Patients showed significantly higher activations in several cortical and subcortical regions during neutral-rated movies, with no differentiation from activations during fun-rated movies. This lower threshold for activating the humor response (even during neutral-rated movies), might represent insight into the mechanisms associated with cataplexy.

• Gustafsson, Miriam K.; Romundstad, Pål Richard; Stafne, Signe Nilssen; Helvik, Anne-Sofie; Stunes, Astrid Kamilla & Mørkved, Siv [Show all 10 contributors for this article] (2019). The effect of an exercise program in pregnancy on vitamin D status among healthy, pregnant Norwegian women: a randomized controlled trial. BMC Pregnancy and Childbirth. 19:76, p. 1–10. doi: 10.1186/s12884-019-2220-z. Full text in Research Archive Show summary

  Background Vitamin D insufficiency is common in pregnant women worldwide. Regular prenatal exercise is considered beneficial for maternal and fetal health. There is a knowledge gap regarding the impact of prenatal exercise on maternal vitamin D levels. The objective of this study was to investigate whether a prenatal exercise program influenced serum levels of total, free and bioavailable 25-hydroxyvitamin D (25(OH)D) and related parameters. This is a post hoc analysis of a randomized controlled trial with gestational diabetes as the primary outcome. Methods Healthy, pregnant women from two Norwegian cities (Trondheim and Stavanger) were randomly assigned to a 12-week moderate-intensity exercise program (Borg perceived rating scale 13–14) or standard prenatal care. The intervention group (n = 429) underwent exercise at least three times weekly; one supervised group training and two home based sessions. The controls (n = 426) received standard prenatal care, and exercising was not denied. Training diaries and group training was used to promote compliance and evaluate adherence. Serum levels of 25(OH)D, parathyroid hormone, calcium, phosphate, magnesium and vitamin D-binding protein were measured before (18–22 weeks′ gestation) and after the intervention (32–36 weeks′ gestation). Free and bioavailable 25(OH)D concentrations were calculated. Regression analysis of covariance (ANCOVA) was applied to assess the effect of the training regime on each substance with pre-intervention levels as covariates. In a second model, we also adjusted for study site and sampling month. Intention-to-treat principle was used. Results A total of 724 women completed the study. No between-group difference in serum 25(OH)D and related parameters was identified by ANCOVA using baseline serum levels as covariates. The second model revealed a between-group difference in levels of 25(OH)D (1.9, 95% CI 0.0 to 3.8 nmol/L; p = 0.048), free 25(OH)D (0.55, 95% CI 0.10 to 0.99 pmol/L; p = 0.017) and bioavailable 25(OH)D (0.15 95% CI 0.01 to 0.29 nmol/L; p = 0.036). No serious adverse events related to regular exercise were seen. Conclusion This study, a post hoc analysis, indicates that exercise may affect vitamin D status positively, and emphasizes that women with uncomplicated pregnancies should be encouraged to perform regular exercise.

• Gustafsson, Miriam; Romundstad, Pål Richard; Stafne, Signe Nilssen; Helvik, Anne-Sofie; Stunes, Astrid Kamilla & Mørkved, Siv [Show all 9 contributors for this article] (2018). Alterations in the Vitamin D endocrine system during pregnancy: A longitudinal study of 855 healthy Norwegian women. PLOS ONE. 13:e0195041(4), p. 1–21. doi: 10.1371/journal.pone.0195041. Full text in Research Archive Show summary

  To ensure optimal calcium accrual in the fetal skeleton, a substantial rise occurs in 1,25-dihydroxyvitamin D (1,25(OH)2D), but is dependent on sufficient 25-hydroxyvitamin (25(OH)D). Large longitudinal studies addressing free 25(OH)D and 1,25(OH)2D during pregnancy are scarce. We aimed to assess levels of and relationship between 25(OH)D, 1,25(OH)2D, vitamin D-binding protein (DBP), parathyroid hormone (PTH), and free 25(OH)D during pregnancy; determinants of vitamin D status; and association between vitamin D indices or PTH and pregnancy outcomes (gestational diabetes mellitus and birthweight). Altogether 855 pregnant Norwegian Caucasian women from Trondheim and Stavanger (latitude 63°N and 58°N) were recruited; 94 were lost to follow-up. The study was originally a randomized controlled trial (2007–2009) with gestational diabetes as primary outcome. Data were collected in second and third trimester. In third trimester, 246 (34%) had vitamin D insufficiency and 52 (7%) deficiency (25(OH)D <50 and <30nmol/L, respectively). During wintertime in third trimester, 61 (47%) from Trondheim and 23 (51%) from Stavanger exhibited vitamin D insufficiency. PTH was elevated in 27 (3.7%). Estimate of change between trimesters was (95% CI): 25(OH)D -1.8 (-2.8 to -0.7) nmol/L, DBP 0.62 (0.57 to 0.66) μmol/L, calculated free 25(OH)D -1.7 (-2.0 to -1.4) pmol/L, PTH 0.81 (0.72 to 0.90) pmol/L, 1,25(OH)2D (sub-analysis) 31.4 (CI 24.7 to 38.2) pmol/L. A decrease in 1,25(OH)2D occurred in 45% of those with vitamin D deficiency, and they also exhibited lower levels than women with adequate vitamin D status. No association of vitamin D indices and PTH with pregnancy outcomes was observed. Women in Trondheim displayed lower 25(OH)D levels, despite minor latitudinal differences. Less than one-fifth adhered to the authorities’ vitamin D recommendations. These findings demonstrate that hypovitaminosis D is prevalent among pregnant women living in northern latitudes, especially during the dark season, and there is an unmet need to ensure adequate vitamin D intake.

• Ueland, Grethe Åstrøm; Methlie, Paal; Øksnes, Marianne; Thordarson, Hrafnkell B; Sagen, Jørn V. & Kellmann, Ralf [Show all 13 contributors for this article] (2018). The short cosyntropin test revisited: new normal reference range using LC-MS/MS. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 103(4), p. 1696–1703. doi: 10.1210/jc.2017-02602. Full text in Research Archive
• Kubiak, Julia Magdalena; Thorsby, Per Medbøe; Kamycheva, Elena & Jorde, Rolf (2018). Vitamin D supplementation does not improve CVD risk factors in vitamin D-insufficient subjects. Endocrine Connections. 7(6), p. 840–849. doi: 10.1530/EC-18-0144. Full text in Research Archive Show summary

  <p><i>Objective</i>: Low serum 25(OH)D levels are associated with cardiovascular disease (CVD) and some of its risk factors. However, in interventional studies, the effects of vitamin D supplementation have been uncertain, possibly due to inclusion of vitamin D-sufficient subjects. Our aim was therefore to examine effects of vitamin D supplementation on CVD risk factors in vitamin D-insufficient subjects.</p> <p><i>Design</i>: Double-blinded randomized controlled trial.</p> <p><i>Methods</i>: A 4-month interventional study with high-dose vitamin D (100,000 IU loading dose, followed by 20,000 IU/week) or placebo with measurements of blood pressure, lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose metabolism parameters (blood glucose, HbA1c, serum human receptors for advanced glycation end products (sRAGE), insulin, C-peptide and HOMA-IR).</p> <p><i>Results</i>: A total of 422 subjects with mean serum 25(OH)D level 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no statistically significant differences between the two groups in any of the measured CVD risk factors, except for a minor increase in sRAGE in the vitamin D group. Stratified analyses of subjects with low baseline serum 25(OH)D levels alone, or combined with blood pressure, lipid and HOMA-IR values above the median for the cohort, did not skew the results in favour of vitamin D supplementation.</p> <p><i>Conclusion</i>: Supplementation with vitamin D in subjects with baseline vitamin D insufficiency does not improve CVD risk factor profile.</p>

• Dahl, Sandra Rinne; Nermoen, Ingrid; Brønstad, Ingeborg; Husebye, Eystein Sverre; Løvås, Kristian & Thorsby, Per Medbøe (2018). Assay of steroids by liquid chromatography-tandem mass spectrometry in monitoring 21-hydroxylase deficiency. Endocrine Connections. 7 (12), p. 1542–1550. doi: 10.1530/EC-18-0453. Full text in Research Archive Show summary

  Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare the use of immunoassays and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the monitoring of patients with classic 21-hydroxylase deficiency (21OHD). Steroid profiles in different mutation groups (genotypes) were also compared. Fifty-five patients with classic 21OHD (38 women) were studied. Blood samples were collected in the morning after an overnight medication fast. LC–MS/MS and immunoassays were employed to assay 17-hydroxyprogesterone (17OHP), testosterone and androstenedione. In addition, 21-deoxycortisol (21DF), 11-deoxycortisol (11DF), corticosterone, deoxycorticosterone, cortisone and cortisol were analyzed by LC–MS/MS. Testosterone, androstenedione and 17OHP levels were consistently lower (by about 30–50%) when measured by LC–MS/MS compared with immunoassays, with exception of testosterone in men. There was a significant correlation between 21DF and 17OHP (r = 0.87, P < 0.001), but three patients had undetectable 21DF. Subjects with no enzyme activity had significantly lower mean 11DF concentrations than subjects with residual activity. The use of LC–MS/MS gives a more specific view of adrenal steroid levels in 21OHD compared with immunoassays, which seem to considerably overestimate the levels of 17OHP and androstenedione. Falsely elevated levels of 17OHP and androstenedione could lead to overtreatment with glucocorticoids.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Agartz, Ingrid; Andreassen, Ole Andreas & Dietrichs, Espen [Show all 9 contributors for this article] (2018). Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives. Sleep. ISSN 0161-8105. 41(10). doi: 10.1093/sleep/zsy145. Full text in Research Archive Show summary

  Study Objectives To assess white matter involvement in H1N1-vaccinated hypocretin deficient patients with narcolepsy type 1 (NT1) compared with first-degree relatives (a potential risk group) and healthy controls. Methods We compared four diffusion tensor imaging–based microstructural indices (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) in 57 patients with NT1 (39 females, mean age 21.8 years, 51/57 H1N1-vaccinated, 57/57 HLA-DQB1*06:02-positive, 54/54 hypocretin-deficient), 54 first-degree relatives (29 females, mean age 19.1 years, 37/54 H1N1-vaccinated, 32/54 HLA-DQB1*06:02-positive), and 55 healthy controls (38 females, mean age 22.3 years). We tested for differences between these groups, for parametric effects (controls > first-degree relatives > patients) and associations in patients (cerebrospinal fluid [CSF] hypocretin-1 and disease duration) and first-degree relatives (HLA-DQB1*06:02 and H1N1-vaccination). We employed tract-based spatial statistics and used permutation testing and threshold-free cluster enhancement for inference. Results Patients with NT1 had a widespread, bilateral pattern of significantly lower FA compared with first-degree relatives and healthy controls. Additionally, patients with NT1 also exhibited significantly higher RD and lower AD in several focal white matter clusters. The parametric model showed that first-degree relatives had intermediate values. Full sample of patients with NT1 showed no significant associations with disease duration or CSF hypocretin-1. Conclusions Our study suggests widespread abnormal white matter involvement far beyond the already known focal hypothalamic pathology in NT1, possibly reflecting the combined effects of the loss of the widely projecting hypothalamic hypocretin neurons, and/or secondary effects of wake/sleep dysregulation. These findings demonstrate the importance of white matter pathology in NT1.

• Aass, Cecilie; Nordheim, Ingrid; Eriksen, Erik Fink; Børnick, Ellen Charlotte; Thorsby, Per Medbøe & Pepaj, Milaim (2017). Establishment of a tear protein biomarker panel differentiating between Graves' disease with or without orbitopathy. PLOS ONE. 12(4). doi: 10.1371/journal.pone.0175274. Full text in Research Archive Show summary

  Background Graves' orbitopathy (GO) is an autoimmune inflammatory ocular complication and one of the most frequent manifestations of Graves' disease (GD). Clinical judgment of GO is subjective sometimes leading to clinical and therapeutic challenges. Better tools to diagnose this severe complication are warranted. Patients and methods The aim of the present study was to evaluate tear levels of LYZ, LACRT and AZGP1 in GD patients with or without GO, as possible biomarkers for GO. Tear samples were collected from GD patients with moderate-to-severe GO (n = 21) and no clinical signs of GO (n = 21). Additionally, 18 GD patients with mild GO and 9 patients without GO were included in a further part of the study. Results Tear levels of LYZ (p < 0.001), LACRT (p = 0.004) and AZGP1 (p = 0.001) were significantly elevated in GD patients with moderate-to-severe GO compared to GD patients without GO. The discriminatory power of the three biomarkers, combined in a panel was confirmed by ROC plot analysis, with an AUC value of 0.93 (sensitivity of 95%; specificity of 80%). Since LYZ showed the best performance in discriminating between GD patients with (moderateto-severe) and without GO (in combination with limited sample volume available), LYZ levels were also measured in tears from GD patients with mild GO and without GO. Significantly higher levels of LYZ were measured in GD patients with mild GO compared to those without GO (p = 0.003).

• Risstad, Hilde; Kristinsson, Jon Adalsteinn; Fagerland, Morten; Roux, Carel W. le; Birkeland, Kåre I. & Gulseth, Hanne Løvdal [Show all 11 contributors for this article] (2017). Bile acid profiles over 5 years after gastric bypass and duodenal switch: results from a randomized clinical trial. Surgery for Obesity and Related Diseases. ISSN 1550-7289. 13(9), p. 1544–1553. doi: 10.1016/j.soard.2017.05.024. Full text in Research Archive
• Krog, Anne Helene; Thorsby, Per Medbøe; Sahba, Mehdi; Pettersen, Erik Mulder; Sandven, Irene & Jørgensen, Jørgen J. [Show all 8 contributors for this article] (2017). Perioperative humoral stress response to laparoscopic versus open aortobifemoral bypass surgery. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 77(2), p. 83–92. doi: 10.1080/00365513.2016.1268264. Full text in Research Archive Show summary

  Minimally invasive surgery seems to reduce hormonal stress response to surgery, but has not previously been examined in major abdominal vascular surgery. Aortic cross-clamping time and operation time is known to be longer in the totally laparoscopic aortobifemoral bypass (LABF) as compared to open aortobifemoral bypass (OABF). The main objective of our study was to measure the hormonal stress response during surgery and aortic cross-clamping in patients undergoing a totally laparoscopic versus an open aortobifemoral bypass. This was a sub-study of a larger randomized controlled multicentre trial. Thirty consecutive patients with severe aortoiliac occlusive disease were randomized to either a laparoscopic (LABF) or an open (OABF) procedure. The surgical stress response was measured by perioperative monitoring of adrenocorticotropic hormone (ACTH), aldosterone, metanephrine and cortisol at eight different time-points. During surgery. there was an increase in all humoral stress markers in both groups. The analysis of covariance showed increased levels of cortisol and ACTH in open group at 24 h time-point as compared to the baseline and this difference was statistically significant between the two groups, which indicate an earlier return to baseline levels in the laparoscopic group. Results from the General Estimated Equations (GEE) model indicate that LABF generates a lower level of metanephrine and higher level of aldosterone as compared to OABF. In conclusion, although they have higher levels of ACTH, aldosterone and cortisol during surgery, the patients operated with a laparoscopic aortobifemoral bypass achieve earlier hormonal homeostasis after surgery compared to open aortobifemoral bypass. This is an Accepted Manuscript of an article published by Taylor & Francis, available online: http://www.tandfonline.com

• Viste, Rannveig; Soosai, Joseph; Vikin, Truls; Thorsby, Per Medbøe; Nilsen, Kristian Bernhard & Knudsen, Stine (2017). Long-Term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy. Neurology: Neuroimmunology and neuroinflammation. 4(5). doi: 10.1212/NXI.0000000000000389. Full text in Research Archive Show summary

  We previously described the possible clinical effects of early monotherapeutic IV-immunomodulation (IVIg) treatment in sporadic1 but not in postH1N1 vaccination narcolepsy type 1 (NT1).2 We report here an early post-H1N1 vaccination NT1 case treated with combined immunomodulation of IVIg and methylprednisolone, and a comparable sporadic NT1 case.

• Jørgenrud, Benedicte Marie; Stene, Lars Christian; Tapia, German; Bøås, Håkon; Pepaj, Milaim & Berg, Jens Petter [Show all 10 contributors for this article] (2017). Longitudinal plasma metabolic profiles, infant feeding, and islet autoimmunity in the MIDIA study. Pediatric Diabetes. ISSN 1399-543X. 18, p. 111–119. doi: 10.1111/pedi.12360. Full text in Research Archive Show summary

  Aims The aim of this study was to investigate the longitudinal plasma metabolic profiles in healthy infants and the potential association with breastfeeding duration and islet autoantibodies predictive of type 1 diabetes. Method Up to four longitudinal plasma samples from age 3 months from case children who developed islet autoimmunity (n = 29) and autoantibody-negative control children (n = 29) with the HLA DR4-DQ8/DR3-DQ2 genotype were analyzed using two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer for detection of small polar metabolites. Results Plasma metabolite levels were found to depend strongly on age, with fold changes varying up to 50% from age 3 to 24 months (p < 0.001 after correction for multiple testing). Tyrosine levels tended to be lower in case children, but this was not significant after correction for multiple testing. Ornithine levels were lower in case children compared with the controls at the time of seroconversion, but the difference was not statistically significant after correcting for multiple testing. Breastfeeding for at least 3 months as compared with shorter duration was associated with higher plasma levels of isoleucine, and lower levels of methionine and 3,4-dihydroxybutyric acid at 3 months of age. Conclusions Plasma levels of several small, polar metabolites changed with age during early childhood, independent of later islet autoimmunity status and sex. Breastfeeding was associated with higher levels of branched-chain amino acids, and lower levels of methionine and 3,4-dihydroxybutyric acid.

• Berents, Teresa Løvold; Carlsen, Karin C. Lødrup; Mowinckel, Petter; Skjerven, Håvard Ove; Rolfsjord, Leif Bjarte & Nordhagen, Live Solveig [Show all 12 contributors for this article] (2017). Weight-for-length, early weight-gain velocity and atopic dermatitis in infancy and at two years of age: A cohort study. BMC Pediatrics. 17:141, p. 1–8. doi: 10.1186/s12887-017-0889-6. Full text in Research Archive Show summary

  Overweight and atopic dermatitis (AD) are major health problems in most industrialised countries, but the relationship between overweight and AD in infants and young children is unclear. We investigated if weight-for-length at birth, in infancy and at two years, as well as early weight-gain velocity, are associated with the development of AD in early life. Methods Cohort study of infants (n = 642), all living in south-east Norway, hospitalized with acute bronchiolitis (n = 404) or recruited from the general population (n = 238), examined at mean age 5.1 months (enrolment) and at a two-year follow-up visit (n = 499; 78%) at mean age 24.6 months. Exposures were weight-for-length (g/cm) at birth, enrolment and two-year follow-up, and early weight-gain velocity (gram/month from birth to enrolment). Excessive weight-for-length was defined as weight-for-length >95th percentile of WHO child-growth standards. Data on weight-for-length at the three time points were obtained for 435, 428 and 473 children. AD was diagnosed according to the Hanifin & Rajka criteria or from a history of physician-diagnosed AD. We performed multivariate analyses with weight-for-length at birth, at enrolment and at the two-year follow-up visit and with early weight gain velocity for the endpoint AD at each visit. Results In adjusted analyses, excessive weight-for-length at enrolment was associated with concurrent AD (OR 3.03; 95% CI 1.23–7.50) and with AD at two years (OR 2.40; 1.11–5.17). In infants without AD, weight-for-length at enrolment increased the risk of AD at two years, with OR being 1.02 (95% CI 1.00–1.04) per increased gram/cm. AD at two years was not associated with concurrent excessive weight-for-length, nor was AD at any time associated with weight-for-length at birth or with early weight-gain velocity. Conclusions The results suggest that overweight in infancy may contribute to the development of AD in early life, highlighting the need for child health-care professionals to address potential overweight and atopic disease when advising infants’ caregivers.

• Sollid, Stina Therese; Hutchinson, Moira Strand; Berg, Vivian; Fuskevåg, Ole-Martin; Figenschau, Yngve Anton & Thorsby, Per Medbøe [Show all 7 contributors for this article] (2016). Effects of Vitamin D binDing protein phenotypes and Vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D. European Journal of Endocrinology (EJE). ISSN 0804-4643. 174(4), p. 445–452. doi: 10.1530/EJE-15-1089. Full text in Research Archive Show summary

  Objective:<br>To determine the relationship between serum total 25-hydroxyvitamin D (25(OH)D), directly measured free 25(OH)D and calculated free 25(OH)D with regard to vitamin D-binding protein (DBP) phenotypes, sex, BMI, age and season, and their interrelationship to vitamin D supplementation.<br>Design, patients and interventions:<br>A randomized controlled trial with 20 000 IU of vitamin D3 per week or placebo for 12 months was designed. A total of 472 subjects, 236 in each of the intervention groups, were included in the analyses.<br>Main outcome measures:<br>Baseline serum concentrations and increases in serum total 25(OH)D, directly measured free 25(OH)D, calculated free 25(OH)D and DBP.<br>Results:<br>Serum total 25(OH)D and DBP concentrations were significantly lower in subjects with the phenotype Gc2/Gc2 compared to phenotypes with the Gc1S allele, and lower in males compared to females. When using directly measured free 25(OH)D, the differences related to DBP phenotypes and sexes were clearly diminished. All calculated free 25(OH)D concentrations were overestimated compared to the directly measured free 25(OH)D. Serum parathyroid hormone showed an inverse correlation with all vitamin D parameters analyzed. The increases after 12 months of vitamin D supplementation were not significantly different for any of the vitamin D parameters regardless of DBP phenotype, sex or age. Supplementation with vitamin D did not affect serum DBP.<br>Conclusion:<br>Direct measurements of free 25(OH)D reduce the differences seen in total 25(OH)D between DBP phenotype groups and sexes, probably caused by differences in DBP concentrations. With conditions affecting serum DBP concentrations, direct measurements of free 25(OH)D should be considered.

• Berents, Teresa Løvold; Carlsen, Karin C. Lødrup; Mowinckel, Petter; Sandvik, Leiv; Skjerven, Håvard Ove & Rolfsjord, Leif Bjarte [Show all 13 contributors for this article] (2016). Vitamin D levels and atopic eczema in infancy and early childhood in Norway: a cohort study. British Journal of Dermatology. ISSN 0007-0963. 175(1), p. 95–101. doi: 10.1111/bjd.14537. Full text in Research Archive
• Aass, Cecilie; Nordheim, Ingrid; Eriksen, Erik Fink; Børnick, Ellen Charlotte; Thorsby, Per Medbøe & Pepaj, Milaim (2016). Comparative proteomic analysis of tear fluid in Graves' disease with and without orbitopathy. Clinical Endocrinology. ISSN 0300-0664. 85(5), p. 805–812. doi: 10.1111/cen.13122. Full text in Research Archive
• Sommer, Christine; Gulseth, Hanne Løvdal; Jenum, Anne Karen; Sletner, Line; Thorsby, Per Medbøe & Birkeland, Kåre I. (2016). Soluble leptin receptor and risk of gestational diabetes in a multiethnic population: A prospective cohort study. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 101(11), p. 4070–4075. doi: 10.1210/jc.2016-2583. Full text in Research Archive
• Pepaj, Milaim; Bredahl, May K. Lyamouri; Gjerlaugsen, Nina & Thorsby, Per Medbøe (2016). Proteomic analysis of the INS-1E secretome identify novel vitamin D-regulated proteins. Diabetes/Metabolism Research and Reviews. ISSN 1520-7552. 32(6), p. 514–521. doi: 10.1002/dmrr.2777. Full text in Research Archive
• Krog, Anne Helene; Sahba, Mehdi; Pettersen, Erik Mulder; Sandven, Irene; Thorsby, Per Medbøe & Jørgensen, Jørgen J. [Show all 8 contributors for this article] (2016). Comparison of the acute-phase response after laparoscopic versus open aortobifemoral bypass surgery: a substudy of a randomized controlled trial. Vascular Health and Risk Management. ISSN 1176-6344. 2016(12), p. 371–378. doi: 10.2147/VHRM.S110600. Full text in Research Archive Show summary

  Purpose: Minimally invasive surgical techniques have been shown to reduce the inflammatory response related to a surgical procedure. The main objective of our study was to measure the inflammatory response in patients undergoing a totally laparoscopic versus open aortobifemoral bypass surgery. This is the first randomized trial on subjects in this population. Patients and methods: This is a substudy of a larger randomized controlled multicenter trial (Norwegian Laparoscopic Aortic Surgery Trial). Thirty consecutive patients with severe aortoiliac occlusive disease eligible for aortobifemoral bypass surgery were randomized to either a totally laparoscopic (n=14) or an open surgical procedure (n=16). The inflammatory response was measured by perioperative monitoring of serum interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP) at six different time points. Results: The inflammatory reaction caused by the laparoscopic procedure was reduced compared with open surgery. IL-6 was significantly lower after the laparoscopic procedure, measured by comparing area under the curve (AUC), and after adjusting for the confounding effect of coronary heart disease (P=0.010). The differences in serum levels of IL-8 and CRP did not reach statistical significance. Conclusion: In this substudy of a randomized controlled trial comparing laparoscopic and open aortobifemoral bypass surgeries, we found a decreased perioperative inflammatory response after the laparoscopic procedure measured by comparing AUC for serum IL-6.

• Pepaj, Milaim; Bredahl, May K. Lyamouri; Gjerlaugsen, Nina; Bornstedt, Mette Eskild & Thorsby, Per Medbøe (2015). Discovery of novel vitamin D-regulated proteins in INS-1 cells: A proteomic approach. Diabetes/Metabolism Research and Reviews. ISSN 1520-7552. 31(5), p. 481–491. doi: 10.1002/dmrr.2629. Full text in Research Archive
• Sørgjerd, Elin Pettersen; Thorsby, Per Medbøe; Torjesen, Peter A; Skorpen, Frank; Kvaløy, Kirsti & Grill, Valdemar Erik Robert (2015). Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study. BMJ Open Diabetes Research & Care. 3(1). doi: 10.1136/bmjdrc-2014-000076. Full text in Research Archive Show summary

  Background It is well known that anti-GAD (glutamic acid decarboxylase) serves as a marker for development of autoimmune diabetes in adults. On the other hand, the clinical implications of anti-GAD positivity in persistently non-diabetic (PND) adults are poorly elucidated. Our aim was to establish the frequency of anti-GAD in PNDs in an all-population-based cohort from the Nord-Trøndelag health study (HUNT) and to prospectively test for associations with glucose tolerance and thyroid autoimmunity. Methods We formed a primary study population (4496 individuals), selected randomly from the age group 20–90 years (50% men/women), who were non-diabetic both at HUNT2 (1995–1997) and HUNT3 (2006–2008). Anti-GAD-positive individuals at HUNT2, together with anti-GAD-negative individuals aged 20–29 years, were retested for anti-GAD positivity at HUNT3. A secondary study population consisted of individuals with type 2 diabetes (T2D, n=349) at HUNT3 who developed diabetes between HUNT2 and HUNT3. Results The frequency of anti-GAD positivity in PND was 1.7% (n=76) at HUNT2. Positivity did not associate with gender, family history of diabetes, or glucose levels, but was associated with thyroid-associated autoimmunity (increased frequency of positivity for anti-TPO (thyroid peroxidase), p<0.002). HLA-DQA1/DQB1, a risk haplotype for autoimmunity, was also associated with anti-GAD positivity in PND. The incidence of anti-GAD positivity was low (0.4%) in the subsample of individuals who were anti-GAD negative in HUNT2. Anti-GAD positivity in PNDs was frequently evanescent, with 54% losing, usually low-grade, positivity between HUNT2 and HUNT3. An evanescent state of autoimmunity as assessed by anti-GAD positivity during “pre-diabetes” in individuals later diagnosed with T2D could, however, not be affirmed. Conclusions Anti-GAD positivity in PND is associated with HLA risk haplotypes and thyroid autoimmunity but not with clinical parameters of diabetes. Fleeting anti-GAD positivity is common; however, results do not support the notion of a history of autoimmunity in T2D in the present cohort.

• Rizvi, Syed Mohammad H.; Veierød, Marit Bragelien; Thorsby, Per Medbøe & Helsing, Per (2015). Vitamin d in Norwegian renal transplant recipients: A longitudinal study with repeated measurements in winter and summer. EJD. European journal of dermatology. ISSN 1167-1122. 25(3), p. 234–239. doi: 10.1684/ejd.2015.2524. Full text in Research Archive
• Pepaj, Milaim & Thorsby, Per Medbøe (2015). Analysis of glycated albumin by on-line two-dimensional liquid chromatography mass spectrometry. Journal of Liquid Chromatography & Related Technologies. ISSN 1082-6076. 38(1), p. 20–28. doi: 10.1080/10826076.2013.864980. Full text in Research Archive
• Aass, Cecilie; Nordheim, Ingrid; Eriksen, Erik Fink; Thorsby, Per Medbøe & Pepaj, Milaim (2015). Single unit filter-aided method for fast proteomic analysis of tear fluid. Analytical Biochemistry. ISSN 0003-2697. 480, p. 1–5. doi: 10.1016/j.ab.2015.04.002. Full text in Research Archive
• Pepaj, Milaim; Gjerlaugsen, Nina; Julien, Kari & Thorsby, Per Medbøe (2014). Tmem27 is upregulated by vitamin D in INS-1 cells and its serum concentrations are low in patients with autoimmune diabetes. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 74(4), p. 358–365. doi: 10.3109/00365513.2014.898322. Full text in Research Archive

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• Kelp, Oskar; Førsvoll, Jostein Andersen; Bischof, Franziska; Stäubert, Claudia; Schöneberg, Torsten & Olsen, Hanne Gro [Show all 11 contributors for this article] (2026). TSHR Gly413Ser in familial nonautoimmune hyperthyroidism: a case report. doi: 10.1515/jpem-2025-0617. Full text in Research Archive Show summary

  Objectives: Familial nonautoimmune hyperthyroidism (FNAH) is a rare disorder caused by activating germline variants in the thyroid-stimulating hormone receptor gene (TSHR) and can mimic antibody-negative Graves’ disease. We report a family with hyperthyroidism and the TSHR variant Gly413Ser and provide clinical, segregation, and functional evidence that this p10-region variant is a novel cause of FNAH. Case presentation: The disorder was recognized after a 15-year-old boy presented with abdominal pain and diarrhea and was found to have suppressed thyrotropin, high-normal free thyroxine, and slightly elevated free triiodothyronine, without thyrotropin receptor antibodies (TRAb) or ophthalmopathy. Family review revealed multigenerational TRAb-negative hyperthyroidism. Genetic testing identified NM_000369.5(TSHR):c.1237G>A, p.(Gly413Ser), initially classified as a variant of uncertain significance. Twelve family members were investigated: nine affected individuals carried the variant, and three unaffected relatives tested negative. Age at diagnosis ranged from 10 to 73 years. Antithyroid drugs gave symptom relief, but relapse occurred after withdrawal; definitive (ablative) treatment was performed in all but one of the affected family members. Basal cyclic adenosine monophosphate (cAMP) production by the Gly413Ser variant was approximately threefold increased, with unchanged inositol 1-phosphate and thyrotropin-stimulated responses. Conclusions: TSHR Gly413Ser is a pathogenic activating variant causing FNAH. Persistent TRAb-negative hyperthyroidism, especially with familial clustering, should prompt TSHR genetic testing and cascade evaluation.

• Solberg, Trine; Skjellegrind, Håvard Kjesbu; Bønaa, Kaare Harald; Thorsby, Per Medbøe; Håheim, Andreas & Ulvik, Øyvind [Show all 7 contributors for this article] (2025). Mann (50+): Dette skjer med kroppen. [Journal]. Nettavisen. doi: https:/www.nettavisen.no/demens/symptomer/helse/mann-50-dette-skjer-med-kroppen/f/5-95-2722292. Full text in Research Archive
• Wang, Qidi; Akdeniz, Cennet; Heck, Ansgar; Bjørk, Mai Britt; Theisen, Ole Rasmus & Eggesbø, Heidi Beate [Show all 16 contributors for this article] (2025). X-bundet hypofosfatemi. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(3). doi: 10.4045/tidsskr.24.0476. Full text in Research Archive Show summary

  X-bundet hypofosfatemi er en sjelden genetisk sykdom som medfører fosfattap i nyrene, redusert mineralisering av tenner og skjelett, deformerte knokler og begrenset mobilitet. Dette har betydelige konsekvenser for helse og livskvalitet. Denne kliniske oversikten gjennomgår anbefalinger for diagnostisering, behandling og oppfølging av voksne med tilstanden.

• Askeland, Frida Bugge; Frøen, Hege; Bolstad, Nils; Thorsby, Per Medbøe; Schjesvold, Fredrik & Marmion, Anne Cathrine W. [Show all 8 contributors for this article] (2024). Monoclonal Insulin Autoimmune Syndrome Successfully Treated With Plasma Cell Directed Therapy. Clinical Lymphoma, Myeloma & Leukemia. ISSN 2152-2650. doi: 10.1016/j.clml.2024.10.005. Full text in Research Archive
• Wammer, Anne Cathrine Parelius; Nermoen, Ingrid; Thorsby, Per Medbøe; Bolstad, Nils; Lima, Kari & Tran, Hoa Thi Tuyet [Show all 7 contributors for this article] (2023). Insulin autoimmune syndrome: not just one but two different diseases with therapeutic implications. Endocrinology, Diabetes and Metabolism Case Reports. 2023(4). doi: 10.1530/EDM-23-0032. Full text in Research Archive Show summary

  We present a young woman with treatment resistant insulin autoimmune syndrome (IAS) with a protracted course. Her serum insulin level was 6945 pmol/l (<160), C-peptide 4042 pmol/L (<1480), anti-insulin antibodies 5305 U/mL (<0.4) were monoclonal IgG kappa. After 12 h of fasting, her blood glucose fell to 1.2 mmol/L. Post-meal blood glucose peaked at 12.2 mmol/L with reactive hypoglycaemia below 2 mmol/L. Frequent meals and continuous blood glucose monitoring were helpful, but further treatments advocated in the literature with prednisolone, rituximab, plasmapheresis, cyclophosphamide and ciclosporin were without beneficial effect. Based on this case and a review of the literature, we propose that IAS is not one but two different diseases with different therapeutic strategies. The first disease, polyclonal IAS, predominates in Asia and is characterized by polyclonal anti-insulin antibodies, association with certain HLA genotypes and other autoimmune conditions, medications and viral infections possibly triggering the disease, a possible female predominance among young patients and a tendency towards spontaneous remission. The other disease, monoclonal IAS, predominates in Caucasians. Typical features are monoclonal anti-insulin antibodies, only weak HLA association, no drug predisposition, no sex difference, rare remission and conventional therapy often being without any clinical effect. We suggest that monoclonal IAS with IgG or IgA anti-insulin antibodies should receive therapy targeting plasma cells rather than lymphocytes.

• Guldhaug, Nora Alicia; Røys, Eirik Åsen; Viste, kristin; Thorsby, Per Medbøe; Sylte, Marit Sverresdotter & Torsvik, Janniche [Show all 11 contributors for this article] (2023). Week-to-week within-subject and between-subject biological variation of copeptin. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. 62(2), p. e29–e33. doi: 10.1515/cclm-2023-0673. Full text in Research Archive
• Trondrud, Liv Monica; Ugland, Cassandra Regine; Ropstad, Erik; Loe, Leif Egil; Albon, Steve & Stien, Audun [Show all 11 contributors for this article] (2023). Author Correction: Stress responses to repeated captures in a wild ungulate (Scientific Reports, (2022), 12, 1, (16289), 10.1038/s41598-022-20270-z). Scientific Reports. 13(1). doi: 10.1038/s41598-023-29744-0. Full text in Research Archive
• Thorsby, Per Medbøe & Gjelstad, Astrid (2021). Når pasienten er idrettsutøver. 7. doi: 10.4045/tidsskr.21.0074. Full text in Research Archive
• Kvammen, Janne Anita; Thomassen, Rut Anne; Kjeserud, Christina; Sæland, Camilla; Godang, Kristin & Thorsby, Per Medbøe [Show all 10 contributors for this article] (2019). Bone health and vitamin D in paediatric intestinal failure patients receiving home parenteral nutrition. Full text in Research Archive
• Gustafsson, Miriam K.; Thorsby, Per Medbøe; Syversen, Unni & Mosti, Mats Peder (2019). The response of vitamin D metabolites to a single bout of resistance and endurance exercise in healthy young adults. Full text in Research Archive
• Methi, Trond & Thorsby, Per Medbøe (2016). T. Methi & P.M. Thorsby svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(14/15), p. 1186–1186. doi: 10.4045/tidsskr.16.0582. Full text in Research Archive
• Methi, Trond & Thorsby, Per Medbøe (2016). Insulinresistens - Kroppens forsvar mot kaloriforgiftning? [Insulin resistance - the body's defence against caloric intoxication?]. 11(136), p. 1015–1017. doi: 10.4045/tidsskr.16.0259. Full text in Research Archive
• Methi, Trond & Thorsby, Per Medbøe (2014). Hvorfor får ikke alle type 2-diabetes? 134(23/24), p. 2284–2286. doi: 10.4045/tidsskr.14.0941. Full text in Research Archive
• Dahl, Sandra Rinne & Thorsby, Per Medbøe (2014). Hvordan måle vitamin D-status? 134(7), p. 729–731. doi: 10.4045/tidsskr.13.0981. Full text in Research Archive

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