Regional Hospital Holstebro

The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.

STUDY DESIGN: A prospective randomized clinical study. OBJECTIVES: To evaluate supplementary pedicle screw fixation (Cotrel-Dubousset) in posterolateral lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: The rationale behind lumbar fusion is to eliminate pathologic motion to relieve pain. To improve fusion rates and to allow reduction, a rigid transpedicular screw fixation may be beneficial, but the positive effect of this may be counter-balanced by an increase in complications. METHODS: The inclusion criteria were severe, chronic low back pain from spondylolisthesis Grades 1 and 2 or from primary or secondary degenerative segmental instability. One hundred thirty patients were randomly allocated to receive no instrumentation (n = 66) or Cotrel-Dubousset instrumentation (n = 64) in posterolateral lumbar fusion. Variables were registered at the time of surgery and at 1 and 2 years after surgery. RESULTS: Follow-up was achieved in 97.7% of the patients. Fusion rates deduced from plain radiographs were not significantly different between instrumented and noninstrumented groups. The functional outcome assessed by the Dallas Pain Questionnaire improved significantly in both groups, and there were no significant differences in results between the two groups, except for significantly better (P < 0.06) functional outcome in relation to daily activities in the instrumented group when neural decompression had been performed. The global patients' satisfaction was 82% in the instrumented group versus 74% in the noninstrumented group (not significant). Fixation of instrumentation increased operation time, blood loss, and early reoperation rate significantly. Patients experienced only a few minor postoperative complications; none were major. Two infections appeared in the Cotrel-Dubousset group. Significant symptoms from misplacement of pedicle screws were seen in 4.8% of the instrumented patients. CONCLUSIONS: Lumbar posterolateral fusion with pedicle screw fixation increases the operation time, blood loss, and reoperation rate, and leads to a significant risk of nerve injury. The functional outcome improves significantly with high patient satisfaction, with or without instrumentation. No significant differences were observed between the two groups in functional outcome and fusion rate. The only gain in functional outcome from instrumentation was found in the daily activity category in patients with supplementary neural decompression. The results of this study do not justify the general use of pedicle screw fixation alone as an adjunct to posterolateral lumbar fusion.

BACKGROUND: Patients with obstructive sleep apnea (OSA) are at increased risk for hypertension. The mechanisms responsible for the development of hypertension are controversial. We hypothesized that patients with OSA had an abnormal 24-h blood pressure (BP) and an abnormal activity in vasoactive hormones, and that both BP and hormones were normalized during treatment with long-term nasal continuous positive airway pressure (CPAP). METHODS: The 24-h BP and plasma levels of the vasoactive hormones (renin, angiotensin II, aldosterone, atrial natriuretic peptide, brain natriuretic peptide, vasopressin, and endothelin-1) were measured in 24 patients with OSA and in 18 control subjects. Thirteen patients with OSA were reexamined after 14 months of CPAP therapy. RESULTS: Patients with OSA had significantly increased BP and heart rate and a reduced nocturnal BP drop. Both angiotensin II (13.3 +/- 1.6 v 7.8 +/- 1.0 pmol/L) and aldosterone (94.0 +/- 9.4 v 62.2 +/- 4.5 pmol/L) were significantly higher in OSA than in control subjects. Positive correlations were found between angiotensin II and daytime BP (systolic: r = 0.49, P <.01; diastolic: r = 0.52, P <.01). The CPAP therapy resulted in a decrease in BP, and this CPAP-induced reduction in BP was correlated with a decrease in both plasma renin (r = 0.76 to 0.92, all P <.01) and plasma angiotensin II concentration (r = 0.58 to 0.81, all P <.05). CONCLUSIONS: Plasma angiotensin II and aldosterone were elevated in OSA, and plasma angiotensin II was correlated with BP. Long-term CPAP reduced BP, and this decrease in BP was correlated with the reductions in plasma renin and angiotensin II levels. We suggest that OSA mediates hypertension, at least in part, via a stimulation of angiotensin II production.

IMPORTANCE: Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear. OBJECTIVE: To systematically review whether supplementation with vitamin D or its analogues reduce BP. DATA SOURCES: We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014. STUDY SELECTION: We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms. DATA EXTRACTION AND SYNTHESIS: We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model. MAIN OUTCOMES AND MEASURES: Difference in SBP and DBP measured in an office setting. RESULTS: We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, -0.8 to 0.8] mm Hg; P=.97; I2=21%) or DBP (effect size, -0.1 [95% CI, -0.6 to 0.5] mm Hg; P=.84; I2=20%). Similar results were found analyzing individual patient data for SBP (effect size, -0.5 [95% CI, -1.3 to 0.4] mm Hg; P=.27; I2=0%) and DBP (effect size, 0.2 [95% CI, -0.3 to 0.7] mm Hg; P=.38; I2=0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy. CONCLUSIONS AND RELEVANCE: Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.

Contemporary medicine is shifting towards person rather than disease-oriented care.1 With increasing life expectancy and the ageing of baby boomers, the proportion over 60 years is growing faster than the overall population, with worldwide estimates reaching 2 billion by 2050 (http://www.un.org/esa/population/publications/worldageing19502050).2 In parallel, acute coronary syndromes (ACS) and atrial fibrillation (AF)—the most frequent indications for dual platelet inhibition or anticoagulation—occur mostly in older patients.2–6 There is general agreement that people ≥75 years can be defined ‘elderly’; however, cutoffs as low as 65 years have been applied to important clinical datasets and risk scores.3,7–10 Moreover, ageing is a continuous process and life-span expansion is deflating (http://www.nber.org/papers/w18407). For these reasons, a threshold to define ‘elderly’ has been intentionally avoided in this document. Of note, over one third of patients admitted with acute myocardial infarction (MI) and two thirds dying from MI are over 75 years, but <7% of patients in ACS trials are reported ≥75 years.11 Older patients have multi-organ changes, increased risk of both bleeding and ischaemic events,3,5,12 frequent comorbidities/comedication, and reduced adherence to prescriptions. Given the challenges of antithrombotic treatment in the elderly, the European Society of Cardiology (ESC) Working Group on Thrombosis gathered a task group to address the topic. Antiplatelet, anticoagulant, and fibrinolytic drugs can prevent, postpone, or attenuate the severity of thrombotic events—namely stroke, transient ischaemic attack (TIA), MI, systemic embolism (SE), deep vein thrombosis (DVT), or pulmonary embolism (PE)—and retard cardiovascular and all-cause death, but at the cost of increased bleeding. The critical conundrum is whether, in the older patient, the benefits outweigh the …

Since Robert Koch described the cause of tuberculosis in 1882, the natural history of the disease after primary infection has been subject to debate. Only approximately 10% of infected individuals develop active disease, which may appear years to decades after infection. Late onset has been attributed to the endogenous reactivation of dormant bacteria. However, this has not been documented by molecular means for latencies of more than a few years. In Denmark, we have recently recultured 205 freeze-dried Mycobacterium tuberculosis strains obtained from 1961 through 1967. These "historical" strains are analyzed by DNA restriction fragment-length polymorphism testing, and their DNA patterns are compared with those of 4008 recently obtained clinical specimens. This has, surprisingly, yielded molecular evidence of M. tuberculosis reactivation after 33 years of latent infection. A father and son who developed tuberculosis in 1961 and in 1994, respectively, were the only patients infected with strains that share an identical DNA pattern.

BACKGROUND: Accelerated perioperative rehabilitation protocols following total hip and knee arthroplasties are currently being implemented worldwide, but the cost-effectiveness of these protocols from a societal perspective is not known. We compared the cost-effectiveness of an accelerated perioperative care and rehabilitation protocol with that of a more standard protocol for patients treated with total hip and knee arthroplasty. METHODS: A cost-effectiveness study was undertaken as a study piggybacked on a randomized clinical trial comparing early outcomes of an accelerated and intensive postoperative rehabilitation regimen with those of a more standard rehabilitation protocol. We assessed eighty-seven patients (forty-two who received the standard protocol and forty-five who received the accelerated protocol) for a total of twelve months. Costs from the time of the patient's visit immediately before the operation to one year postoperatively were calculated with use of activity-based costing analysis. Postoperative quality-adjusted life-years (QALYs) were calculated from validated patient diaries and questionnaires at fifteen time points. The primary objective was to determine whether one intervention was dominant over the other during a twelve-month period or, if neither was dominant, to determine the incremental cost-effectiveness ratio. RESULTS: The result of the randomized clinical trial showed the accelerated intervention to be effective, with a reduction in the length of the hospital stay and a gain in health-related quality of life at the three-month follow-up time point. The cost-effectiveness study showed the accelerated protocol to be significantly less expensive than the standard protocol (p=0.036), with an average reduction in cost of 18,880 Danish kroner (95% confidence interval, 1899 to 38,152) (approximately US $4000). Patients treated with the accelerated protocol following hip arthroplasty had an additional average gain of 0.08 QALY (95% confidence interval, 0.02 to 0.15) compared with the patients who received the standard protocol (p=0.006); this led to a 98% dominance of the accelerated protocol over the standard protocol. No significant or clinically relevant difference in the numbers of QALYs associated with the two protocols was observed for the patients treated with knee arthroplasty. CONCLUSIONS: An accelerated perioperative care and rehabilitation protocol can be both cost-saving and clinically more effective after total hip arthroplasty, whereas it can be cost-saving with no observed significant difference in effect, from a societal perspective, after knee arthroplasty.

BACKGROUND: Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have been associated with incident hypertension. In people living at northern latitudes diminished cholecalciferol synthesis in the winter increases the risk of vitamin D deficiency. We wanted to test the hypothesis that daily cholecalciferol supplementation in the winter lowers BP in patients with hypertension. METHODS: We investigated the effect of 75 µg (3,000 IU) cholecalciferol per day in a randomized, placebo-controlled, double-blind study in 130 hypertensive patients residing in Denmark (56º N). Ambulatory BP (24-h BP) and arterial stiffness were measured before and after 20 weeks of treatment, that took place between October and March. RESULTS: A total of 112 patients (mean age 61 ± 10) with a baseline p-25(OH)D of 23 ± 10 ng/ml completed the study. Compared with placebo, a nonsignificant 3/1 mm Hg (P = 0.26/0.18) reduction was found in 24-h BP. In patients with vitamin D insufficiency (<32 ng/ml) at baseline (n = 92), 24-h BP decreased by 4/3 mm Hg (P = 0.05/0.01). Central BP (CBP) estimated by applanation tonometry and calibrated with a standardized office BP was reduced by 7/2 mm Hg (P = 0.007/0.15) vs. placebo. No differences in carotid-femoral pulse wave velocity (PWV) or central augmentation index (AIx) were found between treatment arms. CONCLUSIONS: Cholecalciferol supplementation, by a dose that effectively increased vitamin D levels, did not reduce 24-h BP, although central systolic BP decreased significantly. In a post-hoc subgroup analysis of 92 subjects with baseline p-25(OH)D levels <32 ng/ml, significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation.

In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.

BACKGROUND: The mechanisms involved in development and maintenance of hypertension in obstructive sleep apnea (OSA) are not clarified. We hypothesize that patients with OSA have an abnormal nocturnal level of some vasoactive hormones during the night. METHODS: We studied 32 patients with OSA and 19 healthy control subjects during The night-time with serial determinations of endothelin-1 (ENDO-1), angiotensin II (Ang II), renin (PRC), aldosterone (ALDO) in plasma, and blood pressure (BP), and oxygen saturation. RESULTS: Patients with OSA had a higher plasma level of ENDO than healthy controls and the mean nocturnal level of ENDO correlated significantly to the apnea-hypopnea index (AHI) as a measure of the severity of OSA. This correlation remained statistically significant after analysis in a general linear model with correction for confounders. Patients with OSA also had a significantly higher BP than healthy controls and the ambulatory BP correlated positively to the AHI in patients with OSA. No significant differences were measured in Ang II, PRC, and ALDO between the two groups. The correlation between AHI and ENDO supports OSA as a stimulus of endothelin release or increased endothelin levels contributing to the severity of OSA. CONCLUSIONS: Endothelin seems to be a pathogenic factor in generating hypertension in OSA.

BACKGROUND: Approximately 12,000 hip and knee replacements were performed in Denmark in 2005. Accelerated perioperative interventions are currently implemented, but there is conflicting evidence regarding the effect. We therefore performed an efficacy study of an accelerated perioperative care and rehabilitation intervention in patients receiving primary total hip replacement, and both total and unicompartmental knee replacement. METHODS: A randomized clinical trial was undertaken in which 87 patients were randomized to either a control group receiving the current perioperative procedure, or an intervention group receiving a new accelerated perioperative care and rehabilitation procedure. Outcome measures were length of stay (LOS) in hospital, and gain in quality of life (QOL) using EQ-5D from baseline to 3-month follow-up. RESULTS: Mean LOS was reduced (p < 0.001) from 8 days (95% CI: 7.1-8.4) in the control group to 5 days (95% CI: 4.2-5.6) in the intervention group. This was accompanied by a greater gain in QOL of 0.08 (95% CI: 0.004-0.16) in the intervention group (p = 0.03). INTERPRETATION: An accelerated perioperative care and rehabilitation intervention in patients undergoing primary total hip replacement, and total or unicompartmental knee replacement is indeed effective-and of advantage to both the hospital and the patient.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

Bleeding is a frequent complication of the management of patients with coronary artery disease (CAD), especially those presenting with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI), and of patients with atrial fibrillation (AF). Randomized trials have shown a risk of major bleeding of 1–8% at 30 days in ACS patients,1–5 and of 2–5% per year in patients with AF treated with oral anticoagulants (OACs).6 Observational studies suggest that bleeding risk is even higher.7 Major bleeding is associated with a subsequent increase in both short- and long-term mortality.7–13 Even minimal bleeding may have prognostic importance because it frequently leads to disruption of antithrombotic therapy.14,15 Hypothetical mechanisms linking bleeding to thrombotic events and death. Numerous risk factors for bleeding are also risk factors for myocardial infarction, stroke and death (large arrows). VTE, venous thromboembolism. Although several recommendations have been published dealing with the acute management of bleeding in patients treated with antithrombotic drugs,22–24 there is an unmet need for guidance on how to manage antithrombotic therapy after bleeding has occurred. Patients with recent bleeding have been excluded from most randomized trials of antithrombotic therapy and rigorous evidence to inform decisions is scarce. While waiting for observational and randomized data to accrue, this consensus paper offers a European perspective on managing antithrombotic therapy after bleeding in patients with CAD and/or AF, including which drugs to stop, which to restart, and when. For the purpose of this document, major bleeding has been defined according to the Bleeding Academic Research Consortium (BARC)25 as BARC type ≥ 3, minor bleeding as BARC type 2 and minimal as BARC type 1. Cessation of antithrombotic therapy has been defined according to Mehran et al.19 as discontinuation (recommended, physician-directed withdrawal), interruption (temporary cessation of antiplatelet treatment due to surgical necessity with reinstitution within 14 days), or disruption (cessation of antiplatelet treatment due to bleeding or non-compliance). Tables 1 and 2 present the authors’ consensus definitions of thrombotic and haemorrhagic risks for CAD and AF patients who develop a bleeding event. Risks are stratified into five categories: low, low-to-moderate, moderate, high, and very high. Definitions are based on simple clinical parameters and validated scores.26,27 Although the value of platelet function testing for predicting ischaemic and bleeding risks was recently demonstrated in a cohort of >20 000 patients,28 personalized treatment based on platelet function and/or genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data.29,30 Ongoing studies further investigate this issue (e.g. NCT01538446, NCT01959451). Consensus definitions of thrombotic risk categories ACS, acute coronary syndrome; AF, atrial fibrillation; BVS, biovascular scaffolds; CAD, coronary artery disease; CHA2DS2-VASc, Cardiac failure, Hypertension, Age ≥75 (2 points), Diabetes, Stroke (2 points)—Vascular disease, Age 65–74, Sex category; DES, drug eluting stent; PCI, percutaneous coronary intervention. Consensus definitions of thrombotic risk categories ACS, acute coronary syndrome; AF, atrial fibrillation; BVS, biovascular scaffolds; CAD, coronary artery disease; CHA2DS2-VASc, Cardiac failure, Hypertension, Age ≥75 (2 points), Diabetes, Stroke (2 points)—Vascular disease, Age 65–74, Sex category; DES, drug eluting stent; PCI, percutaneous coronary intervention. Consensus definitions of recurrent bleeding risk categories To be in the low-risk category for recurrent bleeding, both bleeding source/severity, clinical setting and patient risk factors for bleeding must be low. To be in the high-risk category, it is sufficient that one variable is high risk. HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; PCI, percutaneous coronary intervention. Consensus definitions of recurrent bleeding risk categories To be in the low-risk category for recurrent bleeding, both bleeding source/severity, clinical setting and patient risk factors for bleeding must be low. To be in the high-risk category, it is sufficient that one variable is high risk. HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; PCI, percutaneous coronary intervention. The concomitance of very high thrombotic and very high haemorrhagic risks in a patient with bleeding poses the most difficult treatment decisions. Given the increased risk of thrombotic events after premature cessation of antithrombotic drugs, our consensus is to consider resumption of oral antithrombotic therapy in all situations where there is a clear indication, even in case of major bleeding, as long as the bleeding event is not a life-threatening intracranial or extracranial bleed. When the thrombotic risk is higher than the risk of recurrent bleeding (according to Tables 1 and 2), we suggest continuing antithrombotic therapy. When thrombotic risk is in equipoise with bleeding risk, we suggest only brief or temporary interruption of antithrombotic therapy. When bleeding risk outweighs thrombotic risk, we suggest considering, on a case to case basis, reducing the number and/or dose of antithrombotic drug(s). Whenever possible we strongly suggest recruiting patients into randomized trials or registries designed to address the many dilemmas discussed below. When this is not possible, we suggest applying the guidance provided by this consensus paper. The risk for new cardiovascular events is increased in patients with a recent ACS, especially during the first 3 months, and remains elevated up to 1 year after the acute event.31 The importance of dual antiplatelet treatment (DAPT) with aspirin and a P2Y12 inhibitor up to 1 year for these patients is well established.32 After bleeding, no randomized trials have assessed whether stopping or restarting one or both antiplatelet agents is the best choice. In patients with a recently implanted coronary stent, premature disruption of one or both antiplatelet agents (especially the P2Y12 inhibitor) has been shown to be the strongest predictor of stent thrombosis.33–35 The risk of stent thrombosis increases with longer time off treatment, particularly more than 5 days, and if treatment is stopped within the 1st month after the procedure.33,34,36,37 One-year mortality rates for stent thrombosis remain as high as 10–14%.38,39 In a contemporary registry of over 5000 patients treated with PCI, cardiovascular risk was significantly increased when DAPT cessation was due to non-compliance or bleeding.19 The risk was highest for the first 7 days after the start of disruption, but still high within 30 days.19 Thus, it is important for clinicians to clearly appreciate the heightened risk of ischaemic events following premature cessation of antiplatelet therapy in patients with coronary stents. Recent randomized trials using newer-generation (everolimus- or zotarolimus-eluting) drug-eluting stents (DES) support shortening DAPT duration in patients at high risk of bleeding; in some of these studies, there was no evidence of lower efficacy with 3–6 months of DAPT than with 12 months.32,40,41 Thus, when major bleeding occurs after 3–6 months of DAPT, these studies lend support to discontinuing the P2Y12 inhibitor and continuing aspirin alone, particularly in patients without a prior history of ACS.32 Furthermore, the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent vs. the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERS FREE) trial suggested that a polymer-free biolimus-coated stent may allow even shorter duration of DAPT (1 month).42 Therefore, decisions of whether and when to resume antiplatelet treatment after bleeding should also consider the type of stent(s). While the overall risk of stent thrombosis is lowest with the newest generation DES, the thrombotic risk appears higher with the new bioresorbable vascular scaffolds (BVS), owing to thrombogenicity related to strut thickness and extent of blood contact surface.43,44 Therefore, a longer DAPT duration and a more urgent need for resuming antiplatelet agents after bleeding may be needed with BVS,45 although further studies specifically with this device are required to explore the optimal DAPT duration. In ACS patients treated with the newer P2Y12 inhibitors prasugrel or ticagrelor, there are no data available for resumption after bleeding. The risk of non-CABG related bleeding with these agents is significantly higher compared to clopidogrel. Although the evidence is weak, clopidogrel (which results in less platelet inhibition and a lower risk of spontaneous bleeding) may be used as P2Y12 inhibitor after bleeding has occurred during treatment with prasugrel or ticagrelor, as soon as re-initiation of antiplatelet therapy is possible. The irreversible binding of prasugrel and the reversible binding of ticagrelor should be taken into consideration when deciding when to restart P2Y12 inhibitors in these patients. Dose reduction from 10 to 5 mg od prasugrel or from 90 mg to 60 mg bid ticagrelor is not recommended due to lack of evidence of efficacy in patients with a recent ACS. Of note, however, the two doses of ticagrelor provided similarly high levels of platelet inhibition.46 The bleeding risk is also increased with the thrombin receptor antagonist vorapaxar,47 having an extremely prolonged half-life. Our consensus is that this drug should be discontinued permanently in patients after bleeding has occurred. Trials and registries show that a significant proportion of patients with ACS are treated medically without revascularization for various reasons.48 Such patients on average have worse cardiovascular outcomes compared to those that undergo revascularization.49 The suggestions for antithrombotic therapy after bleeding, outlined for patients treated invasively, largely apply also to patients receiving medical treatment alone, except for the lack of stent thrombosis risk. Two meta-analyses, based mainly on observational data, suggest that single antiplatelet therapy prescribed for secondary prevention in stable CAD patients should be reinitiated within a few days after bleeding. The first analysis includes 50 279 patients receiving aspirin: cessation of, or non-adherence to, aspirin were associated with a three-fold higher risk of major adverse cardiac events compared to its continued use [OR = 3.14 (1.75–5.61), P = 0.0001].50 The risk was magnified in patients with coronary stents.50 The second meta-analysis evaluated patients with perioperative aspirin interruption.51 The mean time to coronary events after withholding aspirin was 8.5 days, with events occurring as early as 5 days after withdrawal. On the other hand, a large randomized trial (POISE-2),52 comparing perioperative aspirin vs. placebo among patients considered at risk of cardiovascular events and undergoing non-cardiac surgery, showed no significant effect of aspirin on the 30-day rate of death or non-fatal myocardial infarction but an increased risk of major bleeding vs. placebo. Of note, less than one third of the POISE-2 population had prior vascular disease and only 23% had CAD. Algorithm for the management of patients with upper gastrointestinal haemorrhage who are using antiplatelet agent(s); modified with permission from Gralnek et al.55 APT, antiplatelet therapy; ASA, aspirin; DAPT, dual antiplatelet therapy; GI, gastrointestinal. For patients at high or very high thrombotic risk (see Table 1: ACS or coronary stenting <30 days) who develop minor or major bleeding, we suggest continuation of low-dose aspirin without interruption. Restarting of the second antiplatelet agent should be considered as soon as possible after stabilization. For patients at moderate thrombotic risk (see Table 1: ACS or PCI with a second generation DES 1–12 months ago) who develop minor or major bleeding, we suggest resumption of low-dose aspirin as soon as bleeding is controlled, preferably within 3 days. Restarting a second antiplatelet agent should be considered if thrombotic risk outweighs recurrent bleeding risk. For patients who develop bleeding while on DAPT within 3 months of new generation DES implantation, we suggest resuming DAPT up to 3 months. If patients develop bleeding more than 3 months after new generation DES implantation and remain at risk of recurrent bleeding, we suggest resumption of only one antiplatelet agent (either aspirin or clopidogrel). In patients with bleeding after BVS implantation, DAPT may be necessary up to 12 months after implantation. Clopidogrel, as less effective but also with a tendency for less bleeding rates, may be used as P2Y12 inhibitor of choice after bleeding has occurred on prasugrel or ticagrelor. The duration of the effect of prasugrel (7–10 days) or ticagrelor (3–5 days)32 should be taken into consideration when deciding when to restart P2Y12 inhibitors in these patients. In patients who develop major bleeding under vorapaxar, we suggest permanent discontinuation of the latter. In medically managed ACS patients who develop major bleeding on DAPT, single antiplatelet therapy may be considered, given the lack of stent thrombosis risk. For patients with stable CAD or ACS who develop upper GI (non-variceal) bleeding, antiplatelet therapy (single or dual) can be continued without interruption if endoscopy identifies low-risk bleeding stigmata (Figure 2). If high-risk bleeding stigmata are identified and bleeding has been controlled by interventional endoscopy, aspirin can be restarted within 3 days.55 If high-risk stigmata are identified in patients on DAPT, resuming the second antiplatelet agent should be on an individual basis after careful weighing potential thrombotic and bleeding risks. Addition of a PPI is recommended in all cases of upper GI bleeding.55,56 PPI should also be used in patients on DAPT at higher than average risk of GI bleeds.32 The pharmacodynamic interaction between PPIs (especially omeprazole) and clopidogrel has not so far been clearly associated with worse clinical outcome, but it is preferred to use PPIs with weaker CYP2C19 inhibition (e.g. pantoprazole).56 Treatment with OACs reduces the risk of stroke and systemic embolism in patients with AF. Cessation of OACs has been shown to be associated with an increased risk of stroke even after short interruptions.57,58 A recent meta-analysis of studies in patients on long-term VKA demonstrated that resumption of warfarin following interruption due to GI bleeding was associated with a reduction in thromboembolic events and mortality without any significant increase in recurrent GI bleeding.59 In a retrospective study of patients with non-valvular AF, restarting warfarin after major GI bleeding was independently associated with decreased mortality as compared to permanent warfarin cessation.60 No significant difference in the incidence of new GI bleeding was found when warfarin was resumed after 1 week vs. 1 month; however, when warfarin was restarted before the 1st week after GI bleeding had passed, the risk of recurrent bleeding was significantly enhanced. Based on these data, in the presence of a clear indication, VKA therapy should be resumed within 1 week following major GI bleeding.60–62 In patients with mechanical heart valves, discontinuation of VKA is associated with a high risk of thrombosis and is generally discouraged. The NOACs have not been tested in AF patients with recent bleeds and the optimal time for restarting NOAC after bleeding is unknown. In a recent study with the antidote idarucizumab for patients on dabigatran presenting a life-threatening bleed or requiring urgent surgery, thrombotic events occurred within 6 days after idarucizumab administration when anticoagulation was not reinitiated.17 It may be reasonable to follow the same advice as for VKA, being aware that the full anticoagulant effect of NOAC occurs sooner (within 1–4 h)63 than with VKA (several days). When (re)starting a NOAC, renal function should be carefully assessed and monitored to avoid drug accumulation. The recommended time interval during follow-up for monitoring of renal function depends on the level of renal function: If creatinine clearance (CrCl) is less than 60 mL/min, then recheck renal function every x months, where x = CrCl/10.63 After major bleeding, however, this interval should be reduced. Some of the NOACs are associated with an increased risk of GI bleeding compared to warfarin.16,64 Switching to warfarin or to a NOAC without an increased risk of GI bleeding compared to warfarin (e.g. apixaban)16,64 may be considered. After extracranial bleeding, OAC should be reinitiated as soon as the cardiovascular thrombotic risks associated with discontinuation are thought to outweigh the risk of re-bleeding with reinitiation, in most cases within 1 week. When (re)starting a NOAC, renal function should be carefully assessed and monitored to avoid drug accumulation. If an antidote (idaruzicumab) has been used to reverse the anticoagulant effect of a NOAC, it is suggested to restart OAC as soon as possible, preferably within 3–4 days if the individual bleeding risk allows. In patients with mechanical heart valves, discontinuation of VKA is associated with a high risk of thrombosis and is discouraged, particularly for valves in the mitral position. NOACs are currently for patients with mechanical heart A in of antithrombotic treatment is patients who present with both AF and most of having an for both DAPT and A of therapy is recommended in most by therapy single up to one OAC is considered DAPT with OAC or significantly increases bleeding of any of the large of possible The is the and anticoagulant therapy in patients with OAC and coronary trial of patients demonstrated that therapy was with to BARC bleeding compared to therapy clopidogrel and and registries have shown The recent in Patients on After Stent study patients receiving VKA who DES implantation and showed that outcomes were if on of VKA and was for 6 or 6 these trials were to ischaemic and the patients were stable and had not a bleed. as an from these studies, we suggest stopping aspirin or clopidogrel when a patient major bleeding during oral antithrombotic therapy. In patients who develop major bleeding on therapy single discontinuation of the antiplatelet agent may be considered before 1 year has passed, as long as the risk is moderate or less is no randomized study comparing VKA vs. NOAC in the setting of AF with and the suggest that can be used in with antiplatelet to choice of antiplatelet the the use of prasugrel or ticagrelor as of The use of ticagrelor in with a NOAC is currently being tested in prospective randomized trials When NOACs are with antiplatelet drugs, the lowest effective dose for stroke prevention should be dabigatran mg bid mg mg or 30 mg only when for dose are The efficacy of bid has not been demonstrated for stroke prevention in AF patients and cannot be recommended for this When patients with non-valvular AF develop bleeding during oral antithrombotic we suggest stopping aspirin or clopidogrel not within the first month of For we suggest a of with VKA and the lowest effective dose for stroke prevention for In patients who develop major bleeding on therapy single discontinuation of the antiplatelet agent may be considered before 1 year has suggest DAPT for 1 year after when a patient with non-valvular AF and a risk of stroke 1 for 2 for bleeding during or antithrombotic therapy. of ACS patients develop intracranial haemorrhage while on antiplatelet is evidence on whether to or resume antiplatelet therapy. consideration of thrombotic and bleeding risk is In restarting therapy after temporary discontinuation should be considered if thrombotic risk, as defined in Table is very high or high. randomized controlled trial of restarting vs. antiplatelet drugs after is is one of the most of occurring in of patients In patients the is whether to restart A of observational studies of patients with heart valves an in patients with mechanical heart valves, anticoagulation with can be restarted as early as 3 days after and to VKA at 7 days without major of For patients without mechanical valves, the is whether to OAC at all after of that a to several observational studies have compared (re)starting vs. OAC after The most studies with various of and a of for OAC and the risks of recurrent or ischaemic events for patients who or restarted from these studies suggest a reduction in ischaemic in recurrent and in death rates associated with restarting although by is given the for the or re-initiation of oral anticoagulation after intracranial AF, atrial fibrillation; intracranial atrial NOAC, antagonist oral oral VKA, = any that not oral anticoagulation no antithrombotic at antiplatelet agent(s); of the evidence The NOACs because of the lower risks of than warfarin in trials of patients with non-valvular AF, but these drugs have not been tested in patients with prior NOACs are currently in the presence of mechanical heart valves given the results of the in Patients with In AF patients with and/or and/or atrial is an randomized trial of vs. no anticoagulation after is and when to restart OAC after an should be on an individual basis, on the thrombotic risk and the risk of recurrent bleeding (Figure between and is needed to decisions. In the of mechanical valves, NOACs may be to warfarin after given lower incidence of among non-valvular AF patients in but efficacy and have still to be in this If one of the NOACs is the lowest effective dose for stroke prevention in AF should be function, and drug should be carefully considered to avoid is a of observational data, and even more so of randomized the risks and of when and how to resume antithrombotic drugs after bleeding in patients with CAD and/or AF. antithrombotic management is largely from randomized trials in patients without a history of bleeding. Although the in these trials are to apply also to patients who have a history of bleeding, the between the reduction in thrombotic events and any increase in recurrent bleeding as well as the for the remain to be The results of trials for this important of patients are The use of antithrombotic drugs and drug for clinicians managing patients who develop bleeding It is that clinicians be aware of the heightened risk of ischaemic events following bleeding and decisions on continuation or of antithrombotic therapy the is to further evidence from randomized we guidance for managing antithrombotic therapy after bleeding when in a clinical trial is not the frequent importance of continuation or early of antithrombotic therapy. of from the from The and other from the from has from and and has in for and is an in and has support from and from and from the and support for from and is the of the or Randomized which is by the has an from and has for in has from the and and from and and from the the the and the from the has as a for and and has been on the for and for and for and has to from the from and from and from and support from The the support from from support and other from the In has a anticoagulant has from and from and and from and from and and from the has support from and from and The

Cryptic diversity within bumblebees (Bombus) has the potential to undermine crucial conservation efforts designed to reverse the observed decline in many bumblebee species worldwide. Central to such efforts is the ability to correctly recognise and diagnose species. The B. lucorum complex (Bombus lucorum, B. cryptarum and B. magnus) comprises one of the most abundant and important group of wild plant and crop pollinators in northern Europe. Although the workers of these species are notoriously difficult to diagnose morphologically, it has been claimed that queens are readily diagnosable from morphological characters. Here we assess the value of colour-pattern characters in species identification of DNA-barcoded queens from the B. lucorum complex. Three distinct molecular operational taxonomic units were identified each representing one species. However, no uniquely diagnostic colour-pattern character state was found for any of these three molecular units and most colour-pattern characters showed continuous variation among the units. All characters previously deemed to be unique and diagnostic for one species were displayed by specimens molecularly identified as a different species. These results presented here raise questions on the reliability of species determinations in previous studies and highlights the benefits of implementing DNA barcoding prior to ecological, taxonomic and conservation studies of these important key pollinators.

During a comprehensive epidemiological study of myasthenia gravis (MG) in Western Denmark 1975-1989, we analyzed the occurrence, clinical characteristics and prognosis of associated autoimmune diseases (AAD) in MG patients. AAD were found in 20 of 212 incident cases (9%) and in 30 of 220 prevalent cases (14%). The most common diseases were: thyroid disorders and rheumatic arthritis. Clinically, it was not possible to identify a subgroup of MG patients with a higher risk of AAD. In most MG patients the AAD occurred before thymectomy. The severity of the AAD was not influenced by thymectomy. The remission rate was lower in MG patients with AAD than in MG patients without AAD suggesting that the autoimmune response in MG patients with AAD is more severe.

OBJECTIVE: To evaluate if fracture risk was increased in patients with Cushing's syndrome due to the increased endogenous cortisol production. DESIGN: Cohort. METHODS: A self-administered questionnaire was mailed to 125 patients with Cushing's syndrome diagnosed between 1985 and 1999 in Denmark. The response of each patient was compared with that of three age- and gender-matched control subjects randomly drawn among respondents to the same questionnaire from the background population. RESULTS: One hundred and four patients (83%) responded. The median age of the patients was 48 years (range 19-85 years). Sixty-eight had pituitary disease, 28 had adrenal disease, four had had both pituitary and adrenal surgery while four had not undergone surgery at the time of the study. The median time from diagnosis to surgery was 0.2 (range 0-3) years. Eighty-six percent were cured following surgery. There was an increased fracture risk within the last 2 years prior to diagnosis (incidence rate ratio 6.0, 95% confidence intervals (CI): 2.1-17.2). More than 2 years prior to diagnosis and following diagnosis there was no difference in fracture risk between patients and controls. The patients had more low-energy fractures than the controls (relative risk 5.4, 95% CI: 1.4-20.1). There was no difference in fracture risk between patients with adrenal or pituitary disease. CONCLUSIONS: Patients with Cushing's syndrome had an increased fracture risk in a narrow time interval before diagnosis, while no increase in fracture risk could be demonstrated after diagnosis and treatment.

Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is reported to occur after major surgery in as many as 20% of patients, elderly patients may especially experience problems in the weeks and months after surgery. Recent studies vary greatly in methods of evaluation and diagnosis of POCD, and the pathogenic mechanisms are still unclear. We evaluated a large uniform cohort of elderly patients in a standardized approach, after major joint replacement surgery (total hip and knee replacement). Patients were in an optimized perioperative approach (fast track) with multimodal opioid-sparing analgesia, early mobilization, and short length of stay (LOS ≤3 days) and discharged to home. METHODS: In a prospective multicenter study, we included 225 patients aged ≥60 years undergoing well-defined fast-track total hip or total knee replacement. Patients had neuropsychological testing preoperatively and 1 to 2 weeks and 3 months postoperatively. LOS, pain, opioid use, inflammatory response, and sleep quality were recorded. The practice effect of repeated cognitive testing was gauged using data from a healthy community-dwelling control group (n = 161). RESULTS: Median LOS was 2 days (interquartile range 2-3). The incidence of POCD at 1 to 2 weeks was 9.1% (95% confidence interval [CI], 5.4%-13.1%) and 8.0% (95% CI, 4.5%-12.0%) at 3 months. There was no statistically significant difference between patients with and without early POCD, regarding pain, opioid use, sleep quality, or C-reactive protein response, although the CIs were wide. Patients with early POCD had a higher Mini Mental State Examination score preoperatively (difference in medians 0.5 [95% CI, -1.0% to 0.0%]; P = 0.034). If there was an association between early POCD and late POCD, the sample size was unfortunately too small to verify this (23.6% of patients with early POCD had late onset vs 6.7% in non-POCD group; risk difference 16.9 (95% CI, -2.1% to 41.1%; P = 0.089). CONCLUSIONS: The incidence of POCD early after total hip and knee replacement seems to be lower after a fast-track approach than rates previously reported for these procedures, but late POCD occurred with an incidence similar to that in previous studies of major noncardiac elective surgery. No association between early and late POCD could be verified.

BACKGROUND: The effect of hysterectomy on sexuality is not fully elucidated and until recently total and subtotal hysterectomies have only been compared in observational studies. AIMS: To compare total abdominal hysterectomy (TAH) to subtotal abdominal hysterectomy (SAH) regarding effects on sexuality. METHODS: In a Danish multicenter trial 319 women were randomized to TAH (n = 158) or SAH (n = 161); 185 women had self-selected TAH (n = 80) or SAH (n = 105) in a simultaneously conducted observational study. Women were followed for 1 year by strict data collection procedures, including postal questionnaires. Results were analyzed by intention to treat (ITT) analyses. RESULTS: No significant differences were observed between TAH and SAH at 1-year follow-up in both the randomized trial and the observational study regarding women's desire for sex, frequency of intercourse, frequency of orgasm, quality of orgasm, localization of orgasm, satisfaction with sexual life, and dyspareunia. None of these sexual variables changed significantly from entry to the 1-year follow-up, apart from dyspareunia, which was significantly (p = 0.009) reduced in both intervention groups. Significant (p < 0.05) predictors for satisfaction with sexual life after hysterectomy were the preoperative satisfaction with sexual life [odds ratio (OR) 32, 95% confidence interval (CI) 10-125], good relationship with partner (OR 50, 95% CI 9-354), physical well-being (OR 0.30, 95% CI 0.09-0.88) and hormone replacement therapy (OR 0.23, 95% CI 0.06-0.78). CONCLUSIONS: Both TAH and SAH significantly reduce dyspareunia without having a negative effect on sexual function. The shift toward SAH seems unwarranted.

This randomized, double-blind, multi-centre study was undertaken to evaluate the efficacy and safety of treatment for 4 weeks with codeine plus paracetamol versus paracetamol in relieving chronic pain due to osteoarthritis of the hip. A total of 158 outclinic patients entered the study. Eighty-three patients (mean age 66 years) were treated with codeine 60 mg plus paracetamol 1 g 3 times daily, and 75 patients (mean age 67 years) with paracetamol 1 g 3 times daily. Ibuprofen 400 mg was prescribed as rescue medication. Due to an unexpected high rate of adverse drug reactions, the study was closed before the planned 400 patients had entered. Over weeks 1-4, 87%, 64%, 61% and 52% of patients in the codeine plus paracetamol group, and 38%, 31%, 22% and 29% of patients in the paracetamol group had one or more adverse drug reactions. Significantly more patients in the codeine plus paracetamol group had adverse drug reactions in each of the 4 weeks. Nausea, dizziness, vomiting and constipation were predominant adverse reactions in the codeine plus paracetamol group. During the first week of treatment, 30 patients (36%) in the codeine plus paracetamol group and 9 (12%) in the paracetamol group dropped out. As evaluated from patients completing the first week of treatment, the pain intensity during that week compared to their baseline pain was significantly lower in the codeine plus paracetamol group than in the paracetamol group. Moreover, during the first week the paracetamol group received rescue medicine significantly more frequently. In conclusion, when evaluated after 7 days of treatment, the daily addition of codeine 180 mg to paracetamol 3 g significantly reduced the intensity of chronic pain due to osteoarthritis of the hip joint. However, several adverse drug reactions, mainly of the gastrointestinal tract, and the larger number of patients withdrawing from treatment means that the addition of such doses of codeine cannot be recommended for longer-term treatment of chronic pain in elderly patients.