Agreement between routinely used immunoassays for thyroid function testing in non-pregnant and pregnant adults.

OBJECTIVE: Thyroid function tests are common biochemical analyses, and agreement between the routinely used immunoassays is important for diagnosis and monitoring of thyroid disease. Efforts are continuously made to align the biochemical assays, and we aimed to evaluate the agreement between immunoassays used in a clinical laboratory setting among non-pregnant and pregnant adults. DESIGN: Cross-sectional study. PARTICIPANTS: Serum samples were obtained from 192 blood donors (non-pregnant adults) and from 86 pregnant women in the North Denmark Region with no known thyroid disease. MEASUREMENTS: Each sample was used for measurement of thyroid-stimulating hormone (TSH) with the routinely used automatic immunoassays in the regional Departments of Clinical Biochemistry (Alinity, Abbott Laboratories, Cobas, Roche Diagnostics, and Atellica, Siemens Healthineers) and reported as the median with 95% confidence interval (95% CI). RESULTS: In nonpregnant adults, the level of TSH was higher with Cobas and Atellica than with Alinity as reflected by median (Alinity: 1.39 mIU/L (95% CI: 1.30-1.51 mIU/L); Cobas: 1.57 mIU/L (95% CI: 1.48-1.75 mIU/L); Atellica: 1.74 mIU/L (95% CI: 1.61-1.83 mIU/L)). Similarly, a trend was seen towards higher median TSH with Cobas than with Alinity among pregnant women (Alinity: 1.90 mIU/L (95% CI: 1.37-2.82 mIU/L); Cobas: 2.33 mIU/L (95% CI: 1.69-3.62 mIU/L)). CONCLUSION: Results of thyroid function tests obtained with different immunoassays were not interchangeable when evaluated among pregnant and non-pregnant adults. The distinct differences are relevant for clinical decision making and emphasize the necessity of clinical laboratory information when different assays are used for diagnosis and monitoring of patients with thyroid disease.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

Maternal hypothyroidism and adverse outcomes of pregnancy.

OBJECTIVE: Hypothyroidism has been associated with pregnancy complications, but uncertainty prevail regarding the severity and the role of thyroid autoimmunity. This study aimed to evaluate adverse pregnancy outcomes by exposure to maternal hypothyroidism and thyroid autoimmunity. DESIGN: Retrospective cohort study. PATIENTS: 14,744 singleton pregnancies from the North Denmark Region Pregnancy Cohort (2011-2015). MEASUREMENTS: Maternal thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab) were retrospectively measured in early pregnancy blood samples (ADVIA Centaur XPT, Siemens Healthineers). Adjusted odds ratio (aOR) with 95% confidence interval (CI) was used to estimate associations between maternal hypothyroidism (TSH cut-offs: 6.0 and 10 mIU/L), thyroid autoimmunity (TPO-Ab cut-off: 60 U/ml, Tg-Ab cut-off: 33 U/ml), and adverse pregnancy outcomes. RESULTS: Pregnancy outcomes were 93.2% live births, 6.5% spontaneous abortions, and 0.3% stillbirths. The frequency of spontaneous abortion was 6.5% when TSH was below 6.0 mIU/L, 6.5% when above 6.0 mIU/L (aOR 1.0 [95% CI: 0.5-2.0]), and 12.5% when above 10 mIU/L (aOR: 2.0 [95% CI: 0.8-5.2]). For outcome of preterm birth, the frequency was 5.4% when TSH was below 6.0 mIU/L, 7.8% when above 6.0 mIU/L (aOR 1.5 [95% CI: 0.7-2.9]), and 11.4% when above 10 mIU/L (aOR: 2.6 [95% CI: 0.9-7.3]). No association was found between thyroid autoantibodies and spontaneous abortion (TPO-Ab: aOR: 1.0 [0.8-1.3], Tg-Ab: 1.0 [0.8-1.2]) or preterm birth (TPO-Ab: aOR: 1.0 [0.8-1.2], Tg-Ab: 0.9 [0.7-1.2]). CONCLUSION: A high frequency of adverse pregnancy outcomes was seen among pregnancies exposed to maternal TSH above 10 mIU/L, whereas no association with thyroid autoantibodies was seen.

Biological variation in thyroid function tests in older adults and clinical implications.

OBJECTIVE: Interpreting thyroid function tests can be challenging due to inherent variation, and the need for tests rises with age. While age-related changes in thyrotropin (TSH) levels are known, the biological variation in older adults remains unclear. DESIGN: We recruited nineteen 65-99-year-old (older adults) without thyroid disease for monthly blood sampling for 1 year. PATIENTS AND MEASUREMENTS: Serum was stored at -20C°, and TSH, total thyroxine (TT4) and total triiodothyronine (TT3) were analysed in random order in a single batch for each participant. Results were compared to test results from 15 euthyroid men aged 24-53 years (younger adults) collected previously using a similar methodology. RESULTS: Interindividual coefficients of variation in older/younger adults were 46.7%/44.0% for TSH, 12.7%/19.5% for TT4 and 14.6%/22.4% for TT3. Intraindividual coefficients of variation (CVI ) were 19.0%/25.4% for TSH, 5.5%/10.8% for TT4 and 6.9%/13.2% for TT3. The index of individuality was below 0.6 for all hormones in all age groups. The number of samples required to determine the homoeostatic set-point at 10% precision in older adults was 14-21 for TSH and 2 for TT4 and TT3. TT4 in older adults was the only parameter in any group with comparable CVI between individuals (p = .22). CONCLUSIONS: CVI for TT4 and TT3 was halved in older compared to younger adults with two tests of TT4 needed to describe the individual set-point. Similar CVI between older adults caused TT4 to provide a reliable estimate of thyroid function, and the added value of measuring thyroxine could improve clinical practice.

Iodine status in Danish pregnant women after an increase in iodine fortification.

OBJECTIVE: Iodine fortification programmes are implemented in many countries and often associated with an increase in population iodine intake. However, the initial attempt may not be sufficient and in Denmark the level of iodine added to salt was increased in 2019. Sparse evidence is available on the impact of such modification in iodine fortification. The aim of this study was to evaluate iodine status in Danish pregnant women in 2021 after this increase in iodine fortification and compare to iodine status in 2012. DESIGN: Cross-sectional study. PATIENTS: Pregnant women in the North Denmark Region referred for routine obstetric ultrasound in 2021. MEASUREMENTS: Participants filled out a questionnaire and delivered a spot urine. Median urinary iodine concentration (UIC) was calculated and assessed according to the recommended range in pregnancy (150-249 µg/L). RESULTS: Altogether 147 pregnant women were included and 88% used iodine-containing supplements. Median UIC was overall 77 µg/L [95% confidence interval (CI): 61-96 µg/L], which was lower than in 2012 (101 µg/L [95% CI: 89-111 µg/L]) (p < 0.001). Considering sources of iodine intake in pregnancy, lower daily intake of dairy products (p = 0.008) and bread (p < 0.001) and a lower content of iodine in the supplement used (p < 0.001) was seen in 2021 compared to 2012. CONCLUSION: Despite an increase in iodine fortification and frequent use of iodine-containing supplements, iodine status in pregnant women in the North Denmark Region was insufficient. Results call for continued monitoring and attention to ensure adequate iodine status during pregnancy in Denmark.

The ratio of neutrophil-to-lymphocyte and platelet-to-lymphocyte and association with mortality in community-acquired pneumonia: a derivation-validation cohort study.

RATIONALE: The ratio of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR) and platelet-to-lymphocyte (PLR) are biomarkers that have shown potential for predicting mortality in several diseases. For patients hospitalized with community-acquired pneumonia (CAP), the prognostic capabilities of these biomarkers are unknown. OBJECTIVE: Investigate whether NLR, MLR or PLR were associated with 90-day mortality in CAP. Further, investigate whether the prediction rule CURB-65 could be improved by adding these biomarkers. METHODS: A derivation-validation study using a Danish multicentre retrospective cohort as the derivation cohort (N = 831) and a European multicentre prospective cohort as the validation cohort (N = 2463). Associations between biomarkers and mortality were assessed using Cox proportional hazard models with adjustments for sex, CURB-65 and comorbidities. A cut-off value for biomarkers was determined using Youden's J Statistics. The performance of CURB-65 with added biomarkers was evaluated using receiver-operating characteristics. RESULTS: In both cohorts increasing NLR and PLR were associated with 90-day mortality. In the derivation cohort, the hazard ratios for NLR and PLR were 1.016 (95% confidence interval (CI) 1.001-1.032, P = 0.038) and 1.001 (95% CI 1.000-1.001, P = 0.035), respectively. Adding these biomarkers to CURB-65 did not improve its performance. CONCLUSIONS: NLR and PLR were associated with 90-day mortality in CAP, but did not improve CURB-65.

Parathyroid hormone reference intervals in adults using second- and third-generation assays.

Parathyroid hormone (PTH) is a routine biochemical analysis, and it varies whether a second- or third-generation assay is used. Information on the levels obtained with different assays and evidence to substantiate local assay-specific reference ranges are important to inform clinical practice. Prior to a shift from the second- to the third-generation PTH assay (Cobas 8000, Roche Diagnostics) in the Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark, a total of 59 EDTA-plasma samples were collected for method comparison (Passing-Bablok). Furthermore, 120 EDTA-plasma samples were randomly obtained from adult blood donors and used for the establishment of reference intervals using the third-generation PTH assay (Cobas 8000, Roche Diagnostics) and two second-generation assays (Atellica, Siemens Healthineers; Alinity, Abbott Laboratories). Method comparison (Cobas 8000, Roche Diagnostics) showed lower levels with the third-generation (y) as compared to the second-generation assay (x) depending on the measurement range (PTH < 10 pmol/L: y = 0.8 (95% CI: 0.7; 0.9) x + 0.3 (95% CI: 0.2; 0.5), PTH ≥ 10 pmol/L: y = 0.6 (95% CI: 0.5; 0.6) x + 3.2 (95% CI: 1.1; 5.2)). Method-specific reference intervals (2.5 and 97.5 percentiles) after the exclusion of samples (n = 31) with 25-hydroxy-vitamin D below 50 nmol/L were: 1.8-8.5 pmol/L (second-generation, Atellica, Siemens Healthineers); 2.4-10.9 pmol/L (second-generation, Alinity, Abbott Laboratories), and 1.8-7.0 pmol/L (third-generation, Cobas 8000, Roche Diagnostics). PTH levels with second- and third-generation assays are not interchangeable. Clinicians should be informed when a laboratory assay is changed, and method-specific reference ranges are needed.

Risk of flare after tapering or withdrawal of biologic/targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis or axial spondyloarthritis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis in sustained remission or with low disease activity. METHODS: Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto's odds ratio (POR) for sparse events and 95% CI. RESULTS: The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation [RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5%] and potentially increased for persistent flare [POR 1.56 (95% CI 0.97, 2.52), I2 = 0%]. Comparing TNF inhibitor (TNFi) withdrawal with continuation, a highly increased flare risk [RR 2.28 (95% CI 1.78, 2.93), I2 = 78%] and increased odds of persistent flare [POR 3.41 (95% CI 1.91, 6.09), I2 = 49%] were observed. No clear difference in flare risk between RA or axSpA was observed. CONCLUSION: A high risk for flare and persistent flare was demonstrated for TNFi withdrawal, whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus tapering seems to be the more favourable approach. REGISTRATION: PROSPERO (CRD42019136905).

Raised mortality in old adults with a history of hyperthyroidism following iodine fortification.

OBJECTIVE: A transient rise in the occurrence of hyperthyroidism ensued the introduction of iodine fortification (IF) of salt in Denmark. Older adults are at risk of complications to hyperthyroidism that could prove fatal to vulnerable individuals. We evaluated the association between thyroid function and mortality in older adults before and after nationwide implementation of IF. DESIGN: Retrospective cohort study. PATIENTS: All 68-year-olds from the general population in the city of Randers were invited to participate in a clinical study in 1988 and followed until death, emigration or end of study (31 December 2017) using Danish registries. MEASUREMENTS: Baseline measures comprised of a questionnaire, physical examination and blood and urine samples. Kaplan-Meier survival curves and Cox regression were used to determine the association between thyroid function and death before and after IF. Time-stratification of results before and after IF was employed due to violation of proportional hazards assumptions in Cox regression. RESULTS: Median urinary iodine concentration was 42 µg/L at baseline consistent with moderate iodine deficiency. Hyperthyroidism (thyrotropin < 0.4 mIU/L) occurred in 37 (9.1%) participants. Kaplan-Meier survival curves showed an increase in mortality among participants with hyperthyroidism after IF. There was no significant association between hyperthyroidism and mortality before IF compared to euthyroid participants, but after IF hyperthyroid subjects had an increased mortality (adjusted hazard ratio: 2.22, 95% confidence interval: 1.44-3.44). CONCLUSIONS: IF was associated with raised mortality among older adults with a history of hyperthyroidism and moderate iodine deficiency. Our results highlight the need for cautious iodine supplementation and for monitoring of IF.

Blood sampling frequency as a proxy for comorbidity indices when identifying patient samples for review of reference intervals.

OBJECTIVES: Indirect data mining methods have been proposed for review of published reference intervals (RIs), but methods for identifying patients with a low likelihood of disease are needed. Many indirect methods extract test results on patients with a low frequency blood sampling history to identify putative healthy individuals. Although it is implied there has been no attempt to validate if patients with a low frequency blood sampling history are healthy and if test results from these patients are suitable for RI review. METHODS: Danish nationwide health registers were linked with a blood sample database, recording a population of 316,337 adults over a ten-year period. Comorbidity indexes were defined from registrations of hospital diagnoses and redeemed prescriptions of drugs. Test results from patients identified as having a low disease burden were used for review of RIs from the Nordic Reference Interval Project (NORIP). RESULTS: Blood sampling frequency correlated with comorbidity Indexes and the proportion of patients without disease conditions were enriched among patients with a low number of blood samples. RIs based on test results from patients with only 1-3 blood samples per decade were for many analytes identical compared to NORIP RIs. Some analytes showed expected incongruences and gave conclusive insights into how well RIs from a more than 10 years old multi-center study (NORIP) performed on current pre-analytical and analytical methods. CONCLUSIONS: Blood sampling frequency enhance the selection of healthy individuals for reviewing reference intervals, providing a simple method solely based on laboratory data without the addition of clinical information.

Modulating Heart Rate Variability through Deep Breathing Exercises and Transcutaneous Auricular Vagus Nerve Stimulation: A Study in Healthy Participants and in Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are associated with an impaired autonomic nervous system and vagus nerve function. Electrical or physiological (deep breathing-DB) vagus nerve stimulation (VNS) could be a potential treatment approach, but no direct comparison has been made. In this study, the effect of transcutaneous auricular VNS (taVNS) and DB on vagal tone was compared in healthy participants and RA or SLE patients. The vagal tone was estimated using time-domain heart-rate variability (HRV) parameters. Forty-two healthy participants and 52 patients performed 30 min of DB and 30 min of taVNS on separate days. HRV was recorded before and immediately after each intervention. For the healthy participants, all HRV parameters increased after DB (SDNN + RMSSD: 21-46%), while one HRV parameter increased after taVNS (SDNN: 16%). For the patients, all HRV parameters increased after both DB (17-31%) and taVNS (18-25%), with no differences between the two types of VNS. DB was associated with the largest elevation of the HRV parameters in healthy participants, while both types of VNS led to elevated HRV parameters in the patients. The findings support a potential use of VNS as a new treatment approach, but the clinical effects need to be investigated in future studies.

Investigating the Dose-Response Relationship between Deep Breathing and Heart Rate Variability in Healthy Participants and Across-Days Reliability in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are associated with autonomic dysfunction, potentially through reduced vagus nerve tone. Vagus nerve stimulation has been proposed as an anti-inflammatory treatment, and it can be performed through deep breathing (DB) exercises. In this study, the dose-response relationship between DB exercises and heart rate variability (HRV) was investigated in healthy participants and reliability across days in patients with RA and SLE. On three separate days, 41 healthy participants performed DB for: 5, 15, or 30 min. On two separate days, 52 RA or SLE patients performed DB with the dose associated with the highest HRV increase in healthy participants. The HRV was estimated from ECG-recordings recorded prior and post the DB exercises. Increases in dose led to larger HRV-responses. Thirty minutes led to the largest HRV-response. In the RA and SLE patients, this dose increased the HRV-parameters consistently across the two days, indicating reliability. DB increases HRV in healthy participants and RA or SLE patients, which indicates stimulation of the vagus nerve. Of the tested durations, 30 min of DB was the optimal period of stimulation. A potential anti-inflammatory effect of DB exercises should be investigated in future studies.

Increased MAO-A Activity Promotes Progression of Pulmonary Arterial Hypertension.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Maternal thyroid disease and adiposity in mother and child.

OBJECTIVE: Thyroid hormones are crucial developmental factors, and thyroid disease in pregnant women is a concern. Overweight and obesity are also important health concerns, and we hypothesized that in utero exposure to maternal thyroid disease could programme the foetus to development of adiposity. DESIGN: Cohort and case-cohort studies. PARTICIPANTS: Pregnant women from the Danish National Birth Cohort and their 7-year-old children. MEASUREMENTS: Maternal thyroid disease (hyperthyroidism and hypothyroidism) was assessed from registrations of diagnoses and treatment (n = 71 706) or from the measurement of thyroid-stimulating hormone (TSH) in a stored blood sample from the early pregnancy (n = 7624). Maternal prepregnancy body mass index (BMI) and child BMI at 7 years of age were used to define overweight and obesity, and associations were evaluated using regression models adjusting for potential confounders. RESULTS: No association was found between maternal thyroid disease in pregnancy and child overweight (hyperthyroidism: adjusted risk ratio (aRR): 1.02 (95% confidence interval (CI): 0.58-1.82); hypothyroidism: 1.31 (0.86-1.97)) or obesity (hyperthyroidism: 0.96 (0.53-1.75); hypothyroidism: 1.25 (0.76-2.05)). On the other hand, pregnant women with hypothyroidism in early pregnancy had a higher risk of being overweight (aRR: 1.20 (95% CI: 1.03; 1.41)) and obese (1.45 (1.07; 1.96)), whereas women with hyperthyroidism had a lower risk of being overweight (0.79 (0.64; 0.98)). CONCLUSIONS: Results provide no evidence that maternal thyroid disease in pregnancy programmes adiposity in the child, but corroborate an association between maternal thyroid disease and adiposity in the mother.

Long-term iodine nutrition is associated with longevity in older adults: a 20 years' follow-up of the Randers-Skagen study.

Iodine intake affects the occurrence of thyroid disorders. However, the association of iodine intake with longevity remains to be described. This led us to perform a 20 years' follow-up on participants from the Randers-Skagen (RaSk) study. Residents in Randers born in 1920 (n 210) and Skagen born in 1918-1923 (n 218) were included in a clinical study in 1997-1998. Mean iodine content in drinking water was 2 µg/l in Randers and 139 µg/l in Skagen. We collected baseline data through questionnaires, performed physical examinations and measured iodine concentrations in spot urine samples. Income data were retrieved from Danish registries. We performed follow-up on mortality until 31 December 2017 using Danish registries. Complete follow-up data were available on 428 out of 430 of participants (99·5 %). At baseline, the median urinary iodine concentration was 55 µg/l in Randers and 160 µg/l in Skagen residents. Participants were long-term residents with 72·8 and 92·7 % residing for more than 25 years in Randers and Skagen, respectively. Cox regression showed that living in Skagen compared with Randers was associated with a lower hazard ratio (HR) of death in both age- and sex-adjusted analyses (HR 0·60, 95 % CI 0·41, 0·87, P = 0·006), but also after adjustment for age, sex, number of drugs, Charlson co-morbidity index, smoking, alcohol and income (HR 0·60, 95 % CI 0·41, 0·87, P = 0·008). Residing in iodine-replete Skagen was associated with increased longevity. This indicates that long-term residency in an iodine-replete environment may be associated with increased longevity compared with residency in an iodine-deficient environment.

Deep Breathing Increases Heart Rate Variability in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus.

BACKGROUND/OBJECTIVE: Autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have been associated with an impaired function of the autonomic nervous system and reduced vagus nerve (VN) tone measured through lower heart rate variability (HRV). Targeting the VN through electrical stimulation has been proposed as a treatment strategy with promising results in patients with RA. Moreover, it has been suggested that the VN can be stimulated physiologically through deep breathing. In this study, the aim was to investigate if the VN can be stimulated through deep breathing in patients with RA and SLE, as measured by HRV. METHODS: Fifty-seven patients with RA and SLE performed deep breathing exercises for 30 minutes in this explorative study. Before the breathing exercise, 2 electrocardiogram recordings were obtained to determine the patient's baseline HRV during rest. After the 30-minute breathing exercise, 5 minutes of electrocardiogram recordings were obtained to determine postintervention HRV and used as a measure of vagal activity. RESULTS: No change was observed in the HRV between the 2 recordings prior the exercise, but the heart rate and HRV significantly decreased and increased, respectively, after the deep breathing exercise. CONCLUSIONS: HRV can be modulated in patients with RA and SLE; this may have implications for future treatment with medications in conjunction with deep breathing. However, the biological and clinical effect of deep breathing must be investigated in future studies.

Right Ventricular Fibrosis.

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.

Thyroid function abnormalities and thyroid autoantibodies in Danish pregnant women.

OBJECTIVE: Abnormal thyroid function in pregnant women is a matter of concern. Knowledge on the occurrence of known and unidentified thyroid function abnormalities in a large unselected cohort of pregnant women is warranted as part of the debate on benefits and risks of routine testing. DESIGN: Cohort study. PARTICIPANTS: A total of 14 323 pregnant women in the North Denmark Region, who had a blood sample drawn as part of the prenatal screening program in early pregnancy (2011-2015). MEASUREMENTS: TSH, free thyroxine, thyroid peroxidase and thyroglobulin antibodies were measured in the stored blood samples using an automatic immunoassay (ADVIA Centaur XPT, Siemens Healthineers). Cohort-, method- and week-specific reference ranges were used for classification of maternal thyroid function, and a cut-off of 60 U/mL was used for thyroid autoantibodies. Information in Danish nationwide registers was used to identify diagnosed and treated maternal thyroid disease. RESULTS: Overall, 15.2% had thyroid function abnormalities in the early pregnancy and 14.9% were thyroid peroxidase and/or thyroglobulin antibody positive. Among women with known thyroid disease (n = 365), the frequency of abnormal thyroid function was 45.7%, and 62.8% in women (n = 172) who received current treatment in the pregnancy. When maternal thyroid disease was diagnosed in the years following pregnancy (n = 313), 46.7% had abnormal thyroid function and 54.3% were thyroid peroxidase and/or thyroglobulin antibody positive in the early pregnancy. CONCLUSION: Thyroid function abnormalities and thyroid autoantibodies were common in Danish pregnant women, particularly in women with known or later diagnosed thyroid disease, which raises concern about inadequately treated and unidentified abnormal thyroid function.

Use of genetic testing for hypolactasia trait in the North Denmark Region.

OBJECTIVE: Lactose intolerance (LI) may be considered in patients with unspecific gastrointestinal symptoms, but there is no clear consensus on when and how to diagnose the disorder. The LCT-13910 CC genotype is associated with acquired primary lactase deficiency (adult-type hypolactasia; ATH). We aimed to describe the number of tests and test results in the North Denmark Region considering patient age, geographical origin and repeated testing. METHODS: Retrospective evaluation of the polymerase chain reaction-based LCT-13910 genotype tests registered in the clinical laboratory information system (LABKA II) with data linkage to Danish nationwide registers. RESULTS: Between 18 May 2007 and 31 December 2018, a total of 23,560 individuals were tested. There was a sevenfold increase in the number of tests performed during the study period. About 9.8% of the tests performed in 2018 were repeated testing in the same individuals. Overall, 8.8% of tested individuals were younger than 5 years, 90.7% were of Danish origin and 5.5% originated from outside of Europe. The LCT-13910 CC genotype was identified in 13.3% of all tested individuals, in 16.0% of children younger than 5 years, in 6.8% of Danish individuals and in 90.9% originating from outside of Europe. CONCLUSIONS: In the North Denmark Region, a marked increase in the use of genetic testing for hypolactasia was observed and repeated testing was frequent. Furthermore, the use of the test and the test results were dependent on patient age and geographical origin. Results inform the debate on when and how to use genetic testing in the diagnosing of LI.

Prenatal exposure to perfluoroalkyl substances and behavioral difficulties in childhood at 7 and 11 years.

BACKGROUND: Perfluoroalkyl substances (PFAS) are suggested to interfere with thyroid hormone during pregnancy and influence fetal neurodevelopment. Epidemiological evidence regarding behavioral difficulties in childhood associated with prenatal PFAS exposure has been inconclusive. OBJECTIVE: We evaluated the association between prenatal PFAS exposure and behavioral difficulties at 7 and 11 years, and investigated the potential mediating role of maternal thyroid hormones. METHODS: Using pooled samples in the Danish National Birth Cohort established between 1996 and 2002, we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child behavioral assessments from the Strength and Difficulties Questionnaire (SDQ), reported by parents at 7 years (n = 2421), and by parents (n = 2070) and children at 11 years (n = 2071). Behavioral difficulties were defined as having a composite SDQ score above the 90th percentile for total difficulties and externalizing or internalizing behaviors. We used logistic regression to estimate the adjusted Odds Ratio (OR) by doubling increase of prenatal PFAS (ng/ml). The possible mediating effect of maternal thyroid function classified based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were evaluated. RESULTS: Prenatal perfluorononanoic acid (PFNA) was consistently associated with total and externalizing behavioral difficulties in all three SDQ measures reported by parents (OR = 1.40, 95% CI: 1.14-1.73 for age 7; OR = 1.27, 95% CI: 1.05-1.53 for age 11) or children (OR = 1.32, 95% CI: 1.11-1.58) while no consistent associations were observed for other types of PFAS. A small magnitude of natural indirect effects via maternal thyroid dysfunction (ORs ranged from 1.01 to 1.03) of several PFAS were observed for parent-reported total and externalizing behaviors at 7 years only. DISCUSSION: Prenatal PFNA exposure was associated with externalizing behavioral difficulties in childhood in repeated SDQ measures at 7 and 11 years. The slight mediating effects of maternal thyroid hormones in early gestation warrant further evaluation.