Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.

Faster lung function decline in people living with HIV despite adequate treatment: a longitudinal matched cohort study.

INTRODUCTION: Chronic lung disease is common among people living with HIV (PLWH). We hypothesised that PLWH receiving antiretroviral therapy (ART) have faster lung function decline than matched controls. METHODS: We performed a prospective matched cohort study by including ART-treated PLWH from the Copenhagen Co-morbidity in HIV Infection Study (n=705) and the INSIGHT Strategic Timing of Antiretroviral Treatment Pulmonary Substudy (n=425) and frequency matched population controls from the Copenhagen General Population Study (n=2895) in a 1:3 ratio. Eligible participants were ≥25 years old and had two spirometry tests separated by at least 2 years of follow-up. Forced expiratory volume in 1 s (FEV1) decline (mL/year) was compared between PLWH and controls using a linear mixed model adjusted for age, sex, ethnicity and smoking status. Effect modification by smoking was investigated in subgroup analyses. RESULTS: The majority of PLWH were virally suppressed (96.1%). The adjusted mean annual decline in FEV1 was faster in PLWH than in controls with 36.4 (95% CI 33.7 to 39.1) vs 27.9 (95% CI 26.9 to 28.8) mL/year, yielding a difference of 8.5 (95% CI 5.6 to 11.4) mL/year. The association between HIV and FEV1 decline was modified by smoking, with the largest difference in current smokers (difference: 16.8 (95% CI 10.5 to 23.0) mL/year) and the smallest difference in never-smokers (difference: 5.0 (95% CI 0.7 to 9.3) mL/year). FEV1 decline >40 mL/year was more prevalent in PLWH (adjusted OR: 1.98 (95% CI 1.67 to 2.34)). CONCLUSION: Well-treated PLWH have faster lung function decline than controls and smoking seems to modify this association, suggesting that smoking may lead to more rapid lung function decline in PLWH than in controls.

Persistent increase over time in oxidatively stress generated RNA and DNA damage in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives - An up to 5-year prospective study.

OBJECTIVES: Increased oxidative stress generated nucleoside damage seems to play a crucial role in bipolar disorder (BD) pathophysiology. It may contribute to accelerated ageing and reduced life expectancy in patients with BD. METHODS: In the five-year prospective "Bipolar Illness Onset study", we investigated repeated measurements of oxidative stress generated RNA and DNA damage in 357 patients with newly diagnosed/first-episode BD (880 visits), 132 of their unaffected first-degree relatives (236 visits) and 198 healthy age- and sex-matched control persons with no personal or first-degree family history of affective disorder (432 visits). Amongst patients with BD, we further investigated associations of oxidative stress generated RNA- and DNA damage with affective phases and measures of illness load. RESULTS: Patients newly diagnosed with BD and their unaffected relatives had higher levels of oxidative stress generated RNA damage than healthy control individuals and these differences persisted over time, whereas DNA damage was less consistently elevated. Neither illness load nor affective phase impacted the levels in patients with BD. CONCLUSIONS: Our findings support elevated oxidative stress generated RNA damage being a trait phenomenon in BD as indicated by persistent increase in RNA damage over time in patients newly diagnosed with BD and in their unaffected first-degree relatives compared with healthy control individuals. We did not detect state alterations in levels of oxidative stress.

Anti-Müllerian hormone and live birth in unexplained recurrent pregnancy loss.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) associated with live birth rate (LBR) in women with unexplained recurrent pregnancy loss (RPL)? DESIGN: Cohort study of women with unexplained RPL attending the RPL Unit, Copenhagen University Hospital, Denmark, between 2015 and 2021. AMH concentration was assessed upon referral, and LBR in the next pregnancy. RPL was defined as three or more consecutive pregnancy losses. Regression analyses were adjusted for age, number of previous losses, body mass index, smoking, treatment with assisted reproductive technology (ART) and RPL treatments. RESULTS: A total of 629 women were included; 507 (80.6%) became pregnant after referral. Pregnancy rates were similar for women with low and high AMH compared to women with medium AMH (81.9, 80.3 and 79.7%, respectively) (low AMH: adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.84-2.47, P = 0.18; high AMH: aOR 0.98, 95% CI 0.59-1.64, P = 0.95). AMH concentrations were not associated with live birth. LBR was 59.5% in women with low AMH, 66.1% with medium AMH and 65.1% with high AMH (low AMH: aOR 0.68, 95% CI 0.41-1.11, P = 0.12, high AMH: aOR 0.96, 95% CI 0.59-1.56, P = 0.87). Live birth was lower in ART pregnancies (aOR 0.57, 95% CI 0.33-0.97, P = 0.04) and with higher numbers of previous losses (aOR 0.81, 95% CI 0.68-0.95, P = 0.01). CONCLUSION: In women with unexplained RPL, AMH was not associated with the chances of live birth in the next pregnancy. Screening for AMH in all women with RPL is not supported by current evidence. The chance of live birth among women with unexplained RPL achieving pregnancy by ART was low and needs to be confirmed and explored in future studies.

The effect of empagliflozin on contractile reserve in heart failure: Prespecified sub-study of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.

Test-retest repeatability and software reproducibility of myocardial flow measurements using rest/adenosine stress Rubidium-82 PET/CT with and without motion correction in healthy young volunteers.

BACKGROUND: Myocardial flow reserve (MFR) assessment with cardiac positron emission computed tomography (PET/CT) is well established, and quantification relies on commercial software packages. However, for reliable use, repeatability and reproducibility are important. The aim of this study was therefore to investigate and compare between scans and software packages the repeatability and reproducibility of 82Rb-PET/CT estimated MFR. METHODS AND RESULTS: Forty healthy volunteers completed two 82Rb-PET/CT rest and adenosine stress scans. syngo.MBF (Siemens), quantitative-gated SPECT (QGS) (Cedars-Sinai), and Corridor4DM (4DM) were used for analyses. Motion correction was available for 4DM. Fifty percent were men and age was 24 ± 4 years (mean ± SD). Repeatability of MFR varied between scans. syngo.MBF: mean difference (95% CI) 0.26 (- 0.03 to 0.54), P = 0.07, limits of agreement (LoA): - 1.43 to 1.95; QGS: 0.19 (- 0.08 to 0.46), P = 0.15, LoA: - 1.38 to 1.76; 4DM: 0.08 (- 0.17 to 0.34), P = 0.50, LoA: - 1.37 to 1.53; and 4DM motion corrected: 0.17 (- 0.17 to 0.51), P = 0.32, LoA: - 1.89 to 2.22. MFR was higher using 4DM +/- motion correction compared with syngo.MBF and QGS (all P < 0.0001). Concordance between syngo.MBF and QGS was high (P = 0.83). CONCLUSIONS: Reproducibility of MFR varied for the different software. The highest concordance between MFRs was found between syngo.MBF and QGS.

The dynamic effects of preoperative intravenous iron in anaemic patients undergoing surgery for colorectal cancer.

AIM: The aim of this study was to describe the dynamic changes in blood work following individual adjusted dosage of intravenously administered iron(III) isomaltoside in a 4-week period prior to surgery in patients with colorectal cancer. METHODS: This was a single-centre, observational cohort study with prospectively collected data, including patients with colorectal cancer receiving preoperative treatment with iron(III) isomaltoside. Blood samples were taken at baseline, 1 week, 2 weeks and 4 weeks after initial treatment. Sixty-two patients were included in the study. RESULTS: Sixty-two patients were included for final analysis. The mean increase in haemoglobin was 0.77 g/dl (95% CI 0.52-1.03 g/dl, P < 0.0001) at week 1, 1.5 g/dl (95% CI 1.21-1.80 g/dl, P < 0.0001) at week 2 and 2.13 g/dl (95% CI 1.71-2.55 g/dl, P < 0.0001) at week 4. Patients with severe anaemia (<9.02 g/dl) showed the largest increase in haemoglobin during the treatment course (2.92 g/dl, 95% CI 2.27-3.58 g/dl, P < 0.0001). Patients with mild anaemia (>10.31 g/dl) did not show a significant increase (0.66 g/dl, 95% CI -0.29-1.61 g/dl, P = 0.17). The mean of transferrin saturation after 4 weeks was 8% (95% CI 6%-10%, P < 0.0001). CONCLUSIONS: After intravenously administered iron, patients with severe anaemia had the most substantial increase in haemoglobin, and the increase was largest after 4 weeks. Patients with mild anaemia did not have an increase in haemoglobin during the treatment course. The vast majority of patients still had iron deficiency at surgery 4 weeks after the initial treatment.

Lectin complement pathway initiators after subarachnoid hemorrhage - an observational study.

BACKGROUND: This exploratory study investigated the time-course of lectin complement pathway (LCP) initiators in cerebrospinal fluid (CSF) and plasma in patients with subarachnoid hemorrhage (SAH), as well as their relationship to delayed cerebral ischemia (DCI) and functional outcome. METHODS: Concentrations of ficolin-1, ficolin-2, ficolin-3, and mannose-binding lectin (MBL) were analyzed in CSF and plasma from patients with SAH. Samples were collected daily from admission until day 9 (CSF; N_PATIENTS = 63, n_SAMPLES = 399) and day 8 (plasma; N_PATIENTS = 50, n_SAMPLES = 358), respectively. Twelve neurologically healthy patients undergoing spinal anesthesia and 12 healthy blood donors served as controls. The development of DCI during hospitalization and functional outcome at 3 months (modified Rankin Scale) were registered for patients. RESULTS: On admission, CSF levels of all LCP initiators were increased in SAH patients compared with healthy controls. Levels declined gradually over days in patients; however, a biphasic course was observed for ficolin-1. Increased CSF levels of all LCP initiators were associated with a poor functional outcome in univariate analyses. This relationship persisted for ficolin-1 and MBL in multivariate analysis after adjustments for confounders (age, sex, clinical severity, distribution and amount of blood on CT-imaging) and multiple testing (1.87 ng/mL higher in average, 95% CI, 1.17 to 2.99 and 1.69 ng/mL higher in average, 95% CI, 1.09 to 2.63, respectively). In patients who developed DCI compared with those without DCI, CSF levels of ficolin-1 and MBL tended to increase slightly more over time (p_interaction = 0.021 and 0.033, respectively); however, no association was found after adjustments for confounders and multiple testing (p-adj_interaction = 0.086 and 0.098, respectively). Plasma ficolin-1 and ficolin-3 were lower in SAH patients compared with healthy controls on all days. DCI and functional outcome were not associated with LCP initiator levels in plasma. CONCLUSION: Patients with SAH displayed elevated CSF levels of ficolin-1, ficolin-2, ficolin-3, and MBL. Increased CSF levels of ficolin-1 and MBL were associated with a poor functional outcome. TRIAL REGISTRATION: This study was a retrospective analysis of samples, which had been prospectively sampled and stored in a biobank. Registered at clinicaltrials.gov ( NCT01791257 , February 13, 2013, and NCT02320539 , December 19, 2014).

Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial.

AIMS: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6]. CONCLUSION: In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed.

Reproducibility of LVEF, LV volumes, and LV mass between Rubidium-82 PET/CT scans in young healthy volunteers using two commercially available software packages.

BACKGROUND: Global functional parameters are available from electrocardiographic gated Rubidium-82 positron emission tomography/computed tomography (82Rb-PET/CT). However, the reproducibility of these data is not clarified. We aimed to investigate reproducibility of left ventricular ejection fraction (LVEF), endsystolic volume (ESV), enddiastolic volume (EDV), and left ventricular (LV) mass between two scans and between two commercially available software packages. METHODS AND RESULTS: Forty healthy young volunteers underwent two 82Rb-PET/CT rest and adenosine stress scans obtaining global functional parameters. Corridor4DM (4DM) and Quantitative Gated SPECT (QGS) were used for analyses. Mean (± SD) age was 24 ± 4 years and 50% were men. High reproducibility of all parameters was found between scans and this was true for both software packages. LVEF at rest with 4DM: mean difference (95% CI) - 1.1 (- 3.0 to 0.8), P = .25, limits of agreement: - 12.8 to 10.6. Significant differences were found between software packages on all functional parameters (P < .0001). CONCLUSION: High reproducibility was found between scans when measuring LVEF, ESV, EDV, and LV mass from 82Rb-PET/CT. However, concordance between parameter measures was poor when comparing the two software packages. Thus, global functional parameter measures are reliable, but the same software package should be used within a study and when comparing absolute values.

Ovarian reserve markers and endocrine profile during oral contraception: Is there a link between the degree of ovarian suppression and AMH?

The ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) are suppressed in varying degree during the use of combined oral contraceptives (COC). Further, long-term use of COC can mask a condition of premature ovarian insufficiency. A desirable clinical tool that could distinguish true low ovarian reserve markers from COC-induced low levels during use of COC is warranted. The aim of this multicenter study including 235 COC users was to assess whether low age-adjusted AMH levels during COC use were linked to concomitant low levels of LH, FSH, estradiol and androgens - as a potential future tool to differentiate between 'false', COC-induced low AMH levels vs. true low AMH. Study population and methods: In total, 235 COC users from the general population aged 19-40 years were included. AMH, AFC and a reproductive hormonal profile were measured during COC intake. Age-adjusted AMH levels (Z-scores) were calculated from a comparison group of 983 non-users of COC. Differences in hormonal profile were tested between women with low versus high age-adjusted AMH-quartiles based on non-parametric Wilcoxon rank sum tests. The outcomes of interest were levels of gonadotropins, estradiol and androgens according to the four the age-adjusted AMH quartiles to find out if women with low age-adjusted AMH levels had a stronger gonadotropin suppression compared with women with higher age-adjusted AMH levels. Mean age of COC users was 30.2 years (SD 3.8), median AMH 14 pmol/l (inter-quartile range (IQR) 8.7-23)), median AFC 16 (IQR 11-25). We found no significant differences across the age-adjusted AMH quartiles in either the levels of gonadotropins, estrogens or androgens, respectively. Thus, the degree of suppression of FSH, LH, androgens and estradiol are unlikely to be a useful tool to differentiate between false low and true low ovarian reserve markers during COC use. Presently, there seems to be no alternative to withdrawal of the COC and to re-test the ovarian reserve after 2-3 months. Trial registration Trial no. NCT02785809 (www.clinicaltrials.gov).

Ovarian reserve markers in women using various hormonal contraceptives.

Objectives: The aim of the study was to assess whether the ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) were lower among women using the progestin-only pill (POP) or levonorgestrel-releasing intrauterine system (LNG-IUS) and similar to the decrease observed in combined oral contraceptive (COC) pill users.Methods: This retrospective study comprised 565 hormonal contraceptive users (COC, POP, LNG-IUS or contraceptive vaginal ring) and 983 non-hormonal contraceptive users, who were seen in two Danish fertility assessment and counselling clinics between 2015 and 2019. Adjusted multiple regression analysis was used to examine the differences in AMH and AFC between hormonal and non-hormonal contraceptive users.Results: Compared with non-hormonal contraceptive users, AMH was 31.1% lower among COC users [95% confidence interval (CI) -39.6%, -25.9%; p < 0.001], 35.6% lower among POP users (95% CI -49.0%, -18.6%; p < 0.001) and 17.1% lower among LNG-IUS users (95% CI -31.4%, 0.002%; p = 0.052); no significant differences were seen among vaginal ring users. Compared with non-hormonal contraceptive users, AFC was 31.3% lower among COC users (95% CI -35.0%, -25.3%; p < 0.001) and 29.7% lower among POP users (-39.1%, -17.9%; p < 0.001); no significant differences were seen among LNG-IUS or vaginal ring users. Ovarian volume was more than 50% reduced among COC and vaginal ring users (p < 0.001) but was unchanged among POP and LNG-IUS users.Conclusion: Assessment of ovarian reserve markers among users of all types of hormonal contraception should be interpreted cautiously and the type of contraceptive method considered.

Emotional demands and exhaustion: cross-sectional and longitudinal associations in a cohort of Danish public sector employees.

PURPOSE: To examine cross-sectional and longitudinal associations between content-related emotional demands at work and exhaustion, and to investigate if these associations were modified by other psychosocial work characteristics. METHODS: In 2007, 4489 Danish public service employees participated in the PRISME study by completing postal questionnaires, and 3224 participated in the follow-up in 2009. Content-related emotional demands were measured by a scale (scored 1 to 5) based on five work-content-related items, and exhaustion was measured with the general exhaustion scale from the Copenhagen Burnout Inventory (CBI) (scored 1 to 5). The cross-sectional and longitudinal associations with exhaustion were analysed in the same model and adjusted for effects of potential confounders. Effect modifications were examined separately for self-reported emotional enrichment, meaningful work, job control, social support at work and quantitative demands. RESULTS: Exhaustion increased with increasing emotional demands, both cross-sectionally and longitudinally. However, although statistically significant, the effect was small. In the longitudinal analysis, a one unit increase in emotional demands was associated with a 0.03 unit (95% CI: 0.01-0.06) increase in exhaustion. We found statistically significant effect modification for three of six potentially modifying work characteristics. The effect of emotional demands on exhaustion was lower for participants with high levels of emotional enrichment (cross-sectionally and longitudinally), high levels of meaningful work (longitudinally), and higher for high levels of quantitative demands (cross-sectionally). CONCLUSIONS: Increasing content-related emotional demands were associated with increasing levels of exhaustion, cross-sectionally and longitudinally. This effect was reduced if the work was experienced as emotionally enriching and meaningful.

Magnetic Resonance Imaging: A New Tool to Optimize the Prediction of Fetal Anemia?

INTRODUCTION: The false-positive rate in the prediction of fetal anemia is 10-15%. We investigated if a new, noninvasive MRI method used as a supplement to ultrasound could improve the prediction. METHODS: Fetuses suspected of anemia and controls were scanned in a 1.5-tesla MRI scanner 1-4 times during pregnancy. Cases were scanned before and after intrauterine blood transfusion with a T1-mapping MRI sequence in a cross-section of the umbilical vein. RESULTS: Inclusion of 8 cases and 11 controls resulted in 10 case scans (2 cases were included twice) and 33 control scans. In controls, the T1 relaxation time was 1,005-1,391 ms; in cases with severe anemia, 1,505-1,595 ms, moderate anemia 1,503-1,525 ms, and no/mild anemia 1,245-1,410 ms. After blood transfusions, values dropped to 1,123-1,288 ms. The mean value in moderate and severe anemic cases was 275 ms higher than in controls (95% CI 210-341 ms, p < 0.0001), and after blood transfusion it was comparable to controls (3 ms, 95% CI -62 to 68 ms, p = 0.934). A 1,450-ms cut-off would have identified all cases in need of blood transfusion with no false-positive cases. CONCLUSIONS: Our findings indicate a potential for this new MRI method to improve the prediction of fetal anemia as a supplement to ultrasound.

Mortality in Women Treated With Assisted Reproductive Technology-Addressing the Healthy Patient Effect.

In previous studies, investigators have reported reduced mortality among women undergoing assisted reproductive technology (ART) treatment, possibly related to selection of healthy women into ART treatment. Our aim in this study was to explore the impact of relevant selection factors on the association between ART treatment and mortality and to explore effect modification by parity. Women treated with ART in fertility clinics in Denmark during 1994-2009 (n = 42,897) were age-matched with untreated women from the background population (n = 204,514) and followed until December 31, 2010. With adjustment for relevant confounders, the risk of death was lower among ART-treated women during the first 2 years after ART treatment (hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.63, 0.74), but there was no apparent difference after 10 years (HR = 0.92, 95% CI: 0.79, 1.07). Having children prior to ART treatment was associated with markedly reduced mortality (HR = 0.45, 95% CI: 0.38, 0.53), possibly due to better health among fertile women. While the frequencies of previous medical and psychiatric diagnoses among ART-treated and untreated women were similar, differences in disease severity could explain the reduced mortality among ART-treated women, as poor prognosis would make initiation of ART treatment unlikely. The survival advantage among ART-treated women is likely a selection phenomenon rather than a biological phenomenon.

Adrenal Suppression in Infants Treated with Topical Ocular Glucocorticoids.

PURPOSE: To analyze the incidence of adrenal suppression and the glucocorticoid (GC) dose per kilogram body weight given in infants treated with standard protocol for topical ophthalmic GCs after congenital cataract surgery. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: All children younger than 2 years of age who underwent operation for congenital cataract between January 2011 and May 2015 in 1 center. METHODS: Patient charts were reviewed to collect data on results and timing of a standard corticotropin (adrenocorticotropic hormone [ACTH]) stimulation test and GC dose per kilogram body weight. MAIN OUTCOME MEASURES: Incidence of adrenal suppression in children tested on GC treatment. Glucocorticoid dose per kilogram body weight. RESULTS: Among 26 consecutive infants, 15 (58%) were tested while they were still on GC treatment. Ten of these 15 infants (67%) had adrenal suppression, 2 of whom had obvious clinical signs of Cushing's syndrome and 1 of whom had signs of Addisonian crises during general anesthesia. Eleven of the 26 infants (42%) were tested at a median time of 21 days (range, 6-89) after treatment cessation, and they all had normal test results. Children with suppressed adrenal function had received cumulative GC doses per body weight that were significantly higher the last 5 days before testing compared with children with normal test results. Infants with adrenal suppression were treated with hydrocortisone replacement therapy. Adrenal function recovered after a median of 3.1 months (range, 2.3 months to 2.3 years). CONCLUSIONS: Two thirds of the infants tested during treatment with a standard GC protocol after congenital cataract surgery showed adrenal suppression. There was a significant association between the cumulative daily dose of GCs and the test result. Because adrenal suppression is a serious but treatable condition, we recommend a systematic assessment of adrenal function in infants treated with doses of topical ocular GCs comparable to our regimen and careful evaluations of other treatment regimens.

Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR): tumor expression patterns and prognostic value in oral cancer.

BACKGROUND: Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhibit enhanced expression in many types of cancers, and have been investigated as potential biomarkers for targeted strategies and prognostication. The aim of the study was to investigate the expression patterns of uPAR, TF and EGFR and their potential prognostic value in OSCC. METHODS: Immunohistochemical expression of uPAR, TF and EGFR in tumor resection specimens from 191 patients with primary OSCC was analyzed. Overall (OS) and disease-free survival (DFS) was calculated. Associations between biomarker expression, clinicopathological factors and patient survival was analyzed using the Cox proportional hazards model for univariate and multivariate analysis, log rank and Kaplan-Meier statistics. RESULTS: uPAR and TF exhibited a highly tumor-specific expression pattern while EGFR also showed expression in normal tissues outside the tumor compartment. The overall positive expression rate of uPAR, TF and EGFR was 95%, 58% and 98%, respectively. High uPAR expression across the entire cohort was negatively associated with OS (p = 0.031, HR = 1.595 (95%CI 1.044-2.439)) in univariate analysis. The 5-year OS for high and low uPAR expression was 39% and 56%, respectively. The expression of TF and EGFR was not associated with survival outcome. CONCLUSIONS: This study may suggest that uPAR and TF could potentially be attractive targets for molecular imaging and therapy in OSCC due to high positive expression rates and tumor-specific expression patterns. High uPAR expression was significantly associated with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer.

Prolonged perceived stress and saliva cortisol in a large cohort of Danish public service employees: cross-sectional and longitudinal associations.

PURPOSE: It is well known that acute stress can lead to a transient increase in cortisol secretion, but the effects of prolonged stress on cortisol secretion are uncertain. This study examines the cross-sectional and longitudinal associations between prolonged perceived stress and salivary cortisol. METHODS: In 2007, 4467 Danish public service employees participated in a study of stress and mental health, and 3217 participated in a follow-up in 2009. Perceived stress during the past 4 weeks was assessed by Cohen's four item perceived stress scale. Participants were asked to collect saliva 30 min after awakening and at approximately 20:00 in the evening. The cortisol dependence on perceived stress was examined in regression analyses adjusted for effects of potential confounders. We adjusted for a large variation in saliva sampling times by modelling the time trajectory of cortisol concentrations in the morning and in the evening and examined if they were influenced by perceived stress. RESULTS: Perceived stress had no statistically significant effects on the level or time trajectory of morning or evening cortisol, neither cross-sectionally nor longitudinally. The 1 month prevalence of frequently perceived stress was low, approximately 2.5%. CONCLUSION: Our results did not support the hypothesis that prolonged perceived stress is associated with the level or time trajectory of morning or evening salivary cortisol.

Inter- and intra-rater agreement in the assessment of the vascularity of spinal metastases using digital subtraction angiography tumor blush.

Background Preoperative embolization is based on the preoperative digital subtraction angiography (DSA) tumor blush, and as such is considered the "gold standard" for determining tumor vascularity. However, to our knowledge reliability studies evaluating vascularity ratings of DSA tumor blush in spinal metastases have not been published previously. Purpose To evaluate inter- and intra-rater agreement in the assessment of the vascularity of spinal metastases using DSA tumor blush. Material and Methods This reliability study included 46 patients with symptomatic metastatic spinal cord compression requiring surgery. DSA data stored in the hospital picture archiving and communication system (PACS) from the participants of a randomized controlled trial were used. Inter- and intra-rater agreement on vascularity assessment using DSA tumor blush according to a three-step ordinal scale was evaluated: no hypervascularity; moderate hypervascularity; and pronounced hypervascularity. The statistical analysis was based on the linear weighted kappa's for multiple raters that extend Cohen's κ. Three raters and κ = 0.2 in the null hypothesis implied that the power of the study was 0.96. Results Inter- and intra-rater agreements were moderate in rating the vascularity of spinal metastases and the agreements were significantly higher than the κ = 0.20 in the null hypothesis ( P = 0.0002 and P = 0.0001). The κ value for inter-rater agreement was 0.57 (95% confidence interval [CI], 0.41-0.72) and for intra-rater agreement 0.55 (95% CI, 0.38-0.71). Conclusion There is moderate inter-rater and intra-rater agreement in classifying the vascularity of spinal metastases on a three-step ordinal scale for DSA tumor blush.

Neonatal Risk Factors for Treatment-Demanding Retinopathy of Prematurity: A Danish National Study.

PURPOSE: One goal of the study was to identify "new" statistically independent risk factors for treatment-demanding retinopathy of prematurity (ROP). Another goal was to evaluate whether any new risk factors could explain the increase in the incidence of treatment-demanding ROP over time in Denmark. DESIGN: A retrospective, register-based cohort study. PARTICIPANTS: The study included premature infants (n = 6490) born in Denmark from 1997 to 2008. METHODS: The study sample and the 31 candidate risk factors were identified in 3 national registers. Data were linked through a unique civil registration number. Each of the 31 candidate risk factors were evaluated in univariate analyses, while adjusted for known risk factors (i.e., gestational age [GA] at delivery, small for gestational age [SGA], multiple births, and male sex). Significant outcomes were analyzed thereafter in a backward selection multiple logistic regression model. MAIN OUTCOME MEASURES: Treatment-demanding ROP and its associations to candidate risk factors. RESULTS: Mechanical ventilation (odds ratio [OR], 2.84; 95% confidence interval [CI], 1.99-4.08; P < 0.01) and blood transfusion (OR, 1.97; 95% CI, 1.20-3.14; P = 0.01) were the only new statistically independent risk factors, in addition to GA at delivery, SGA, multiple births, and male sex. Modification in these prognostic factors for ROP did not cause an increase in treatment-demanding ROP. CONCLUSIONS: In a large study population, blood transfusion and mechanical ventilation were the only new statistically independent risk factors to predict the development of treatment-demanding ROP. Modification in the neonatal treatment with mechanical ventilation or blood transfusion did not cause the observed increase in the incidence of preterm infants with treatment-demanding ROP during a recent birth period (2003-2008).