An estimate of the need for continuous glucose monitoring in type 2 diabetes with intensive insulin treatment in secondary healthcare.

AIM: To estimate the proportion of persons with type 2 diabetes (T2DM) receiving intensive insulin treatment in the secondary healthcare who could be candidates for continuous glucose monitoring (CGM), based on different HbA1c criteria. For comparison, the results are also presented as proportion of persons with type 1 diabetes (T1DM) in the same region. PATIENTS AND METHODS: In the Central Denmark Region, we identified all persons with T1DM (n = 6179) and T2DM (n = 4315) who had a minimum of one contact to a diabetes outpatient clinic from September 2021 to September 2022. Insulin regimen and HbA1c measured after a minimum of 2 months with a stable insulin regimen were retrieved from the healthcare administrative electronic platform used in the region. RESULTS: The numbers of persons with T1DM and T2DM with HbA1c meeting the criteria were 5145 and 3090, respectively. The fraction of T2DM with basal-bolus insulin was 35.3%, and the fraction with basal-bolus insulin and HbA1c >53 (7%) mmol/mol or >58 (7.5%) mmol/mol was 20.5% and 16.6%, respectively. These proportions correspond to 19.4%, 14.4% and 11.7% of the persons with T1DM in the same geographical area. CONCLUSION: The proportion of persons with T2DM in secondary healthcare undergoing intensive insulin treatment who could be candidates for CGM corresponded to only a minor fraction of persons with T1DM in the same region, irrespective of any HbA1c criteria applied.

One size does not fit all: universal cuff overestimates oscillometric blood pressure in persons with large arm circumference.

OBJECTIVE: Some brachial cuffs for oscillometric blood pressure (BP) measurement are claimed to cover a wide range of upper-arm circumferences; however, their validation is rarely conducted. Our aim was to compare oscillometric BP measurements obtained with a universal cuff with those obtained with an appropriately sized cuff. METHODS: We utilised the Microlife B6 Connect monitor, conducting oscillometric BP measurements in a random sequence with both a universal cuff (recommended for arm circumferences from 22 to 42 cm) and an appropriately sized cuff (medium for circumference 22-32 cm and large for 32-42 cm). We included 91 individuals with an arm circumference of 22-32 cm and 64 individuals with an arm circumference of 32-42 cm. RESULTS: For arm circumferences > 32 cm, systolic and diastolic BP measured with the universal cuff was higher than that measured with the large cuff (systolic 6.4 mmHg, 95% confidence interval [CI]). 3.9-8.8, diastolic 2.4 mmHg, 95%CI, 1.2-3.7, p < 0.001 for both). Overestimation of BP with the universal cuff was statistically significant after correcting for the sequence of measurements. No statistical difference was found between the universal cuff and medium cuff for circumferences in the 22-32 cm range. The bladder size in the universal cuff matched the dimensions of the medium-sized cuff; however, the cuff was larger. CONCLUSION: Overestimation of BP measured with a universal cuff in persons with large arm circumferences is clinically important. It poses the risk of unnecessary initiation or intensification of antihypertensive medication in persons using the universal cuff.

What is the context?Clinical guidelines recommend individualisation of the size of the cuff used for blood pressure measurement according to the circumference of the upper arm.Many blood pressure monitors are sold with a single "universal" cuff claimed to cover a wide range of upper arm sizes.We compared blood pressure obtained with the Microlife B6 Connect monitor and a "universal" cuff with the results obtained with individual sized cuffs (medium size for arm circumference between 22 and 32 cm and large size for arm circumference between 32 and 42 cm).What is new?In persons with large upper arm circumference is the systolic blood pressure 6.4 mmHg higher and the diastolic blood pressure 2.4 mmHg higher with the universal cuff than with the individual-sized large cuff.What is the impact?The universal cuff overestimates blood pressure in persons with large arm circumference.

Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study).

BACKGROUND: Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease. METHODS: Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013. SETTING: Exploratory sub-study using data from the nationwide EPICOM study. PARTICIPANTS: Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code. MAIN OUTCOME MEASURES: This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples. RESULTS: We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX). CONCLUSIONS: These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

Increased use of diagnostic CT imaging increases the detection of stage IA lung cancer: pathways and patient characteristics.

BACKGROUND: At Silkeborg Regional Hospital, Denmark, the number of stage IA lung cancer increased after implementation of increased use of CT investigations and a corresponding reduction in chest X-ray. The aim of the present study was to understand the changes in referral pathways, patient characteristics and imaging procedures behind the observed increase in early-stage lung cancer. METHODS: The referral and imaging pathways for all patients diagnosed with lung cancer in 2013-2018 were described based on manually curated information from the electronic health care systems and staging information from the Danish Lung Cancer Registry. We compared the clinical characteristics of patients diagnosed in 2013-2015 and in 2016-2018 after implementation of a change in the use of low dose CT scan (LDCT). For patients diagnosed in 2016-2018, stage IA lung cancer were compared to higher stages using univariable logistic regression analysis. RESULTS: Five hundred and forty-seven patients were diagnosed with lung cancer in 2013-2018. Stage IA constituted 13.8% (34/247) in 2013-2015, and 28.3% (85/300) in 2016-2018. Stage IA patients in 2016-2018 were characterised by more comorbidity, fewer packyears and tended to be older than patients with higher stages. In 2016-2018, the largest proportion of stage IA patients (55%) came from within-hospital referrals. The majority of these lung cancers were detected due to imaging procedures with other indications than suspicion of lung cancer. The proportion of stage IA increased from 12% (12/99) to 36% (47/129) (p < 0.001) for hospital referrals and from 17% (22/129) to 23% (38/165) for GP referrals (p = 0.21). The imaging procedures contributing to the increase in stage IA was contrast enhanced CT (22%¸11/51), LDCT (35%; 18/51) and X-ray followed by LDCT (25%; 13/51). CONCLUSION: The increased access to LDCT for patients referred from general practice and the increased hospital requested CT activity resulted in an increase in the number of stage IA lung cancers. Incidental findings on imaging performed for diagnostic purposes unrelated to suspicion of lung cancer contributed a large proportion of the increase.

Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females.

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X-chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome-wide DNA-methylation and RNA-expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA-methylation and RNA-expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome-wide DNA-methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X-chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

Impaired aortic distensibility and elevated central blood pressure in Turner Syndrome: a cardiovascular magnetic resonance study.

BACKGROUND: Women with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection. METHODS: Fifty-seven women with Turner Syndrome (48 years [29-66]) and thirty-six age- and sex-matched controls (49 years [26-68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta. RESULTS: Mean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = - 0.44, P = 0.005) and a higher central systolic blood pressure (r = - 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS. CONCLUSION: Aortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( #NCT01678274 ) on September 3, 2012.

Continuous measurement of aortic dimensions in Turner syndrome: a cardiovascular magnetic resonance study.

BACKGROUND: Severity of thoracic aortic disease in Turner syndrome (TS) patients is currently described through measures of aorta size and geometry at discrete locations. The objective of this study is to develop an improved measurement tool that quantifies changes in size and geometry over time, continuously along the length of the thoracic aorta. METHODS: Cardiovascular magnetic resonance (CMR) scans for 15 TS patients [41 ± 9 years (mean age ± standard deviation (SD))] were acquired over a 10-year period and compared with ten healthy gender and age-matched controls. Three-dimensional aortic geometries were reconstructed, smoothed and clipped, which was followed by identification of centerlines and planes normal to the centerlines. Geometric variables, including maximum diameter and cross-sectional area, were evaluated continuously along the thoracic aorta. Distance maps were computed for TS and compared to the corresponding maps for controls, to highlight any asymmetry and dimensional differences between diseased and normal aortae. Furthermore, a registration scheme was proposed to estimate localized changes in aorta geometry between visits. The estimated maximum diameter from the continuous method was then compared with corresponding manual measurements at 7 discrete locations for each visit and for changes between visits. RESULTS: Manual measures at the seven positions and the corresponding continuous measurements of maximum diameter for all visits considered, correlated highly (R-value = 0.77, P < 0.01). There was good agreement between manual and continuous measurement methods for visit-to-visit changes in maximum diameter. The continuous method was less sensitive to inter-user variability [0.2 ± 2.3 mm (mean difference in diameters ± SD)] and choice of smoothing software [0.3 ± 1.3 mm]. Aortic diameters were larger in TS than controls in the ascending [TS: 13.4 ± 2.1 mm (mean distance ± SD), Controls: 12.6 ± 1 mm] and descending [TS: 10.2 ± 1.3 mm (mean distance ± SD), Controls: 9.5 ± 0.9 mm] thoracic aorta as observed from the distance maps. CONCLUSIONS: An automated methodology is presented that enables rapid and precise three-dimensional measurement of thoracic aortic geometry, which can serve as an improved tool to define disease severity and monitor disease progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier - NCT01678274 . Registered - 08.30.2012.

Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.

BACKGROUND: An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. METHODS AND RESULTS: Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 µmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 µmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. CONCLUSION: MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.

Osteoprotegerin in Turner syndrome - relationship to aortic diameter.

BACKGROUND: Cardiovascular disease is a cardinal trait of Turner syndrome (TS), causing half of the threefold excess mortality. As osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease, this cross-sectional and prospective study aimed at elucidating OPG levels in TS and its relationship to aortic diameter as well as validated cardiovascular risk markers. METHODS: Adult women with TS (n = 99) were examined thrice (mean follow-up 4·7 ± 0·5 years), and 68 age-matched healthy female controls were examined once. Aortic diameter was assessed by cardiovascular magnetic resonance. Twenty-four-hours blood pressure monitoring and biochemical assessments were also performed. RESULTS: Osteoprotegerin levels (median with range) were lower in TS (777 [326-10 569] ng/l) compared with controls (979 [398-1987] ng/l; P < 0·05) and did not change during follow-up. The OPG concentration was higher among women with TS older than 50 years of age (996 [542-4996] vs 756 [326-10 569] ng/l; P < 0·05) with a trend towards a higher OPG in TS who were on antihypertensive medication (938 [490-2638] vs 752 [326-10 569] ng/l; P = 0·09). Contrary to controls, OPG levels correlated with BSA-indexed aortic diameter (r = 0·31-0·45; P < 0·05), age (r = 0·29; P < 0·05) and high-sensitivity C-reactive protein (r = 0·23; P = 0·02) and inversely with BSA (r = -0·20; P < 0·05), weight (r = -0·23; P < 0·05) and plasma oestradiol levels (r = -0·34; P < 0·05). CONCLUSION: Levels of OPG are lower in TS and correlate with aortic diameter, age, BSA, weight and oestradiol in TS, but not controls. Future studies are needed to assess whether OPG may serve as a biomarker of aortic or cardiovascular disease in TS.

Short QTc interval in males with klinefelter syndrome-influence of CAG repeat length, body composition, and testosterone replacement therapy.

BACKGROUND: Klinefelter syndrome (KS) is a sex chromosomal aneuploidy (47,XXY) affecting 1/660 males. Based on findings in Turner syndrome, we hypothesized that electrocardiogram (ECG) abnormalities would be present in males with KS. OBJECTIVE: To investigate ECGs in males with KS and compare with controls. METHODS: Case control study of 62 males with KS and 62 healthy males matched on age. The primary outcome parameter was a difference in the ECG presentation between the two groups. The ECGs were analyzed by one blinded examiner (intraobserver variability 0.2-2.1%). The QT-interval was measured using "teach-the-tangent" method excluding the U-wave. QTc was calculated using Bazett's equation, Hodges' equation, and a linear regression model. Body mass index, abdominal fat, and muscle mass as well as sex hormone levels were secondary parameters. The prevalence of mutations in genes related to short QT syndrome was determined in participants with a QTc < 330 ms. RESULTS: Compared to controls, the QTc-interval was shorter (P = 0.02-0.06) in males with KS depending on the applied correction method. QTc was shortest among testosterone (T)-treated males with KS, while untreated and thus hypogonadal KS had QTc interval comparable to controls. No mutations in genes related to short QT syndrome were found. CONCLUSION: We found short QTc interval in males with KS, with further shortening of the QTc interval by T. These results suggest that genes on the X chromosome could be involved in regulation of the QTc interval and that T treatment may aggravate this mechanism.

Can internal medicine specialists diagnose functional somatic disorders (FSDs)? Training and comparison with FSD specialists.

BACKGROUND: Functional somatic disorders (FSD) are a common problem across medical settings and remain challenging to diagnose and treat. Many patients with FSD undergo sequential and unnecessary extensive diagnostic work-up, which is costly for society and stressful for patients. Previous studies have shown that the empirically based FSD diagnostic entities are interrater reliable and stable over time. OBJECTIVE: The aim of this study was to investigate whether internists who have received adequate training and with sufficient time per patient could diagnose FSD. DESIGN: This was a prospective diagnostic accuracy study. The study was conducted from May 2020 to April 2022. PARTICIPANTS: The study included 27 consecutive patients referred by their general practitioner to a non-psychiatric diagnostic clinic for assessment of physical symptoms on suspicion of FSD. INTERVENTIONS: The internists received a 30-hour training course in the use of a tailored version of the SCAN interview. MAIN MEASURES: The main outcome measure was the agreement between the diagnoses of the internists and the reference diagnoses made by specialists in FSD on the basis of the full SCAN interview. KEY RESULTS: The interrater agreement between the internists and the FSD experts was substantial for any FSD (kappa = 0.63) as well as multi-organ vs. single-organ FSD (kappa = 0.73), indicating good diagnostic agreement. CONCLUSIONS: Internists with proper training and sufficient time (3-4 hours) per patient can proficiently diagnose FSD employing a tailored version of the SCAN interview for use in a non-psychiatric diagnostic setting.

Decision support to general practice in choice of chest imaging for patients with pulmonary symptoms.

INTRODUCTION: The choice of chest imaging for patients with respiratory problems is based on risk profile and symptoms. In 2018-2020, GPs in the catchment area of Silkeborg Regional Hospital, Denmark, were offered direct referral for either X-ray or low-dose computed tomography (LDCT) of the chest for patients with respiratory symptoms who did not meet the criteria for a contrast-enhanced CT (CECT) of the chest and upper abdomen as part of the lung cancer referral pathway. The aim of this study was 1) to estimate the percentage of patients referred for LDCT or chest X-ray who met CECT criteria based on the clinical information in the referral letters, and 2) to assess the GPs' response to standard questions regarding the active feedback provided. METHODS: The study was conducted from April to October 2019. Radiographers initially assessed all referrals for X-ray or LDCT, and contacted the GPs if they assessed that symptoms and clinical characteristics justified CECT. RESULTS: In the study period, 1,112 referrals for chest imaging from GPs were received; in 97 cases (9%), the referral information warranted CECT as part of a lung cancer referral package. In 71% (69/97) of these cases, the GP accepted the conversion to CECT; 55 of 73 LDCTs and 14 of 24 X-rays. In 15 cases, the GP adhered to the requested imaging owing to clinical assessment or their agreement with the patient, and in the remaining 13 cases no specific reason was given. CONCLUSION: The feedback provided was well received by GPs and the approach adopted may be a step towards structured decision support to facilitate the choice of chest imaging. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Adrenal incidentalomas and effectiveness of patient pathway transformation.

INTRODUCTION: A total of 10% of older individuals harbour adrenal incidentalomas and need dedicated adrenal CT to exclude malignancy and biochemical evaluation. These investigations tax medical resources, and diagnostic delay may cause anxiety for the patient. We implemented a no-need-to-see pathway (NNTS) in which low-risk patients only attend the clinic if adrenal CT or hormonal evaluation is abnormal. METHODS: We investigated the impact of a NNTS pathway on the share of patients not requiring an attendance consultation, time to malignancy and hormonal clarification, and time to end of investigation. We prospectively registered adrenal incidentaloma cases (n = 347) and compared them with historical controls (n = 103). RESULTS: All controls attended the clinic. A total of 63% of cases entered and 84% completed the NNTS pathway without seeing an endocrinologist; 53% of consultations were avoided. Time-to-event analysis revealed a shorter time to clarification of malignancy (28 days; 95% confidence interval (CI): 24-30 days versus 64 days; 95% CI: 47-117 days) and hormonal status (43 days; 95% CI: 38-48 days versus 56 days; 95% CI: 47-68 days) and a shorter time to end of pathway (47 days; 95% CI: 42-55 days versus 112 days; 95% CI: 84-131 days) in cases than controls (p ≤ 0.01). CONCLUSION: We demonstrated that NNTS pathways may be an efficient way of handling the increased burden of incidental radiological findings, avoiding 53% of attendance consultations and achieving a shorter time to end of pathway. FUNDING: Supported by a grant from Regional Hospital Central Denmark, Denmark. The study was approved by the institutional review boards of all participating hospitals. TRIAL REGISTRATION: Not relevant.

Effect of telemonitoring on readmissions for acute exacerbation of chronic obstructive pulmonary disease: A randomized clinical trial.

INTRODUCTION: Acute exacerbations of chronic obstructive pulmonary disease are associated with high morbidity and mortality. Telemonitoring may reduce the frequency of hospitalization. The aim of this study was to investigate the effect of telemonitoring on hospitalization rates for acute exacerbations of chronic obstructive pulmonary disease. METHODS: Patients were recruited during hospitalization and equally randomized to telemonitoring or usual care. Telemonitoring participants recorded symptoms and monitored oxygen saturation, heart rate, peak expiratory flow, and body weight. Alerts were generated if readings breached thresholds. Acute exacerbations of chronic obstructive pulmonary disease hospitalizations during the 6 months intervention were compared using logistic regression, and time to first hospitalization was assessed using Cox proportional hazard modeling. The incidence rates for acute exacerbations of chronic obstructive pulmonary disease hospitalization were compared using a negative binomial regression model with between-group comparisons expressed as incidence rate ratios. The telemonitoring group was used as reference. RESULTS: A total of 222 patients were randomized. 37/112 (33%) in the control group and 31/110 (28%) in the telemonitoring group experienced acute exacerbations of chronic obstructive pulmonary disease hospitalization during the intervention period, odds ratio of 1.26, confidence interval 0.71-2.23, p = 0.4. No difference was seen in time to first hospitalization, hazard ratio 1.23, CI 0.77-1.99, p = 0.4. The number of hospitalizations in the intervention period was 66 in the control group and 42 in the telemonitoring group, with incidence rate ratio 1.42, confidence interval 1.04-1.95, p = 0.03. Adjustment for dyspnea score, smoking, and cohabitation status did not change the results, incidence rate ratio 1.44, confidence interval 1.05-1.99, p = 0.02. DISCUSSION: Patients who received telemonitoring experienced significantly fewer acute exacerbations of chronic obstructive pulmonary disease hospitalizations, although the overall risk of having at least one hospitalization and the time to first hospitalization was similar between the two groups.

X chromosome dosage and the genetic impact across human tissues.

BACKGROUND: Sex chromosome aneuploidies (SCAs) give rise to a broad range of phenotypic traits and diseases. Previous studies based on peripheral blood samples have suggested the presence of ripple effects, caused by altered X chromosome number, affecting the methylome and transcriptome. Whether these alterations can be connected to disease-specific tissues, and thereby having clinical implication for the phenotype, remains to be elucidated. METHODS: We performed a comprehensive analysis of X chromosome number on the transcriptome and methylome in blood, fat, and muscle tissue from individuals with 45,X, 46,XX, 46,XY, and 47,XXY. RESULTS: X chromosome number affected the transcriptome and methylome globally across all chromosomes in a tissue-specific manner. Furthermore, 45,X and 47,XXY demonstrated a divergent pattern of gene expression and methylation, with overall gene downregulation and hypomethylation in 45,X and gene upregulation and hypermethylation in 47,XXY. In fat and muscle, a pronounced effect of sex was observed. We identified X chromosomal genes with an expression pattern different from what would be expected based on the number of X and Y chromosomes. Our data also indicate a regulatory function of Y chromosomal genes on X chromosomal genes. Fourteen X chromosomal genes were downregulated in 45,X and upregulated in 47,XXY, respectively, in all three tissues (AKAP17A, CD99, DHRSX, EIF2S3, GTPBP6, JPX, KDM6A, PP2R3B, PUDP, SLC25A6, TSIX, XIST, ZBED1, ZFX). These genes may be central in the epigenetic and genomic regulation of sex chromosome aneuploidies. CONCLUSION: We highlight a tissue-specific and complex effect of X chromosome number on the transcriptome and methylome, elucidating both shared and non-shared gene-regulatory mechanism between SCAs.

Clinical care of adult Turner syndrome--new aspects.

Turner syndrome (TS) is characterized by numerous medical challenges during adolescence and adulthood. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) should continue during adult years. These issues are normally dealt with by the paediatrician, but once a TS female enters adulthood it is less clear who should be the primary care giver. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular diseases, as well as the risk of type 2 diabetes, hypertension, osteoporosis, thyroid disease and other diseases. The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. The transition period from paediatric to adult care seems to be especially vulnerable and the proper framework for transition has not yet been established. Likewise, no framework is in place for continuous follow-up during adult years in many countries. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as growth hormone and oxandrolone treatment for increasing height, are becoming well founded. Osteoporosis, diabetes, both type 1 and 2, hypothyroidism, obesity and a host of other endocrine diseases and conditions are seen more frequently in TS. Prevention, intervention and proper treatment is only just being recognized. Hypertension is frequent and can be a forerunner of cardiovascular disease. The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. Proper care during adulthood should be studied and a framework for care should be in place, since most morbidity potentially is amenable to intervention. In summary, TS is a condition associated with a number of diseases and conditions which need the attention of a multi-disciplinary team during adulthood.

Sex chromosome aneuploidies give rise to changes in the circular RNA profile: A circular transcriptome-wide study of Turner and Klinefelter syndrome across different tissues.

Purpose: The landscape of circular RNAs (circRNAs), an important class of non-coding RNAs that regulate gene expression, has never been described in human disorders of sex chromosome aneuploidies. We profiled circRNAs in Turner syndrome females (45,X; TS) and Klinefelter syndrome males (47,XXY; KS) to investigate how circRNAs respond to a missing or an extra X chromosome. Methods: Samples of blood, muscle and fat were collected from individuals with TS (n = 33) and KS (n = 22) and from male (n = 16) and female (n = 44) controls. CircRNAs were identified using a combination of circRNA identification pipelines (CIRI2, CIRCexplorer2 and circRNA_finder). Results: Differential expression of circRNAs was observed throughout the genome in TS and KS, in all tissues. The host-genes from which several of these circRNAs were derived, were associated with known phenotypic traits. Furthermore, several differentially expressed circRNAs had the potential to capture micro RNAs that targeted protein-coding genes with altered expression in TS and KS. Conclusion: Sex chromosome aneuploidies introduce changes in the circRNA transcriptome, demonstrating that the genomic changes in these syndromes are more complex than hitherto thought. CircRNAs may help explain some of the genomic and phenotypic traits observed in these syndromes.

Incidence and Clinical Presentation of Pheochromocytoma and Sympathetic Paraganglioma: A Population-based Study.

CONTEXT: Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers. OBJECTIVE: We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study. METHODS: We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data. RESULTS: SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare. CONCLUSION: Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a "new" group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.

[The no-need-to-see process for adrenal incidentalomas].

With wider application and technical improvement of imaging the discovery of adrenal incidentalomas (AI) has been skyrocketing. AI need to be investigated for evidence of hormonal hypersecretion and malignancy, and this causes a considerable use of health resources and potential medicalisation. In the "no-need-to-see" process, the clinical assessment of the citizen will only take place, if the diagnostic tests are abnormal. In this review, we examine the predictive values of imaging and paraclinical testing and argue, that normal test results in people without extra-adrenal cancer exclude disease.