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Background: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). Objective: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. Methods: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. Results: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (β=−0.003 mmHg [95% CI, −0.005 to −0.0003]) and diastolic blood pressure (β=−0.002 mmHg [95% CI, −0.004 to −0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (β=−0.01 mmHg [95% CI, −0.01 to −0.004]) and diastolic blood pressure (β=−0.010 mmHg [95% CI, −0.012 to −0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. Conclusions: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Introduction: The hypothalamic-pituitary-adrenal axis function in depression has been the subject of considerable interest, and its function has been tested with a variety of methods. We investigated associations between saliva cortisol at awakening and the 24-h urine cortisol output, both measured at study baseline, with endpoint depression scores. Methods: Patients were admitted to a psychiatric inpatient ward with a major depressive episode and were started on fixed duloxetine treatment. They delivered saliva samples at awakening and 15, 30, and 60 min post-awakening and sampled urine for 24 h. Subsequently, they started a daily exercise program maintained for a 9-week period. Clinician-rated depression severity was blindly assessed with the Hamilton Depression Rating 6-item subscale (HAM-D6). The cortisol awakening response was quantified by the area under the curve with respect to the ground (AUCG) and with respect to the rise (AUCI) using saliva cortisol levels in the 1-h period after awakening. Analysis of expected associations between depression severity, AUCG, AUCI, exercise, and 24-h cortisol output was performed in a general linear model. Results: In all, 35 participants delivered saliva or 24-h urine samples. The mean age was 49.0 years (SD = 11.0) with 48.6% females with a mean baseline HAM-D6 score of 12.2 (SD = 2.3). In a statistical model investigating the association between HAM-D6 at week 9 as a dependent variable and AUCI, concurrent HAM-D6, gender, smoking, and exercise volume as covariates, we found a significant effect of AUCI, concurrent HAM-D6, and exercise. The following statistics were found: AUCI (regression coefficient 0.008; F value = 9.1; p = 0.007), concurrent HAM-D6 (regression coefficient 0.70; F value = 8.0; p = 0.01), and exercise (regression coefficient −0.005; F value = 5.7; p = 0.03). The model had an R2 of 0.43. The association between HAM-D6 endpoint scores and the AUCI showed that higher AUCI values predicted higher HAM-D6 endpoint values. The association between HAM-D6 endpoint scores and the exercise level showed that a high exercise level was associated with lower HAM-D6 endpoint values. Conclusion: The results thus showed that high AUCI values predicted less improvement of depression and high exercise levels predicted more improvement of depression. These findings need to be confirmed in larger samples to test if more covariates can improve prediction of depression severity.

Prostate cancer (PCa) is the second most common cancer in men and one of the leading causes of cancer-related deaths. Early detection is the key to successful treatment and provides the greatest chance to cure the patient. Currently, early detection involves screening for prostate-specific antigen levels in blood, which is not a tumor-specific biomarker. There is a critical need to develop clinically useful methods for screening for more reliable biomarkers. Here, we introduce an electrochemical biosensor that measures the concentrations of the amino acids tyrosine and tryptophan, and propose it as a possible diagnostic and prognostic tool for PCa. The limits of detection of tyrosine and tryptophan using the electrochemical sensors were 1.15 and 1.13 μmol/L in 1:10 urine: PBS, respectively. This study is the first to present electrochemical measurements of tyrosine and tryptophan directly in patient urine samples. We demonstrated an inverse correlation between the measured electrochemical signals and the severity of PCa. The most notable observation was a significant difference between controls and metastatic PCa patients (P ≤ 0.001). This observation was further validated using Liquid-Chromatography-Mass Spectrometry. Our data provides the basis for further research with electrochemical measurements of tyrosine and tryptophan as potential biomarkers for PCa.

Introduction During pregnancy, maternal cortisol levels are increased 3-fold by the third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates the balance between cortisol and cortisone levels. Perfluoroalkyl substances (PFAS) have been reported to inhibit 11β-HSD1 and more potently 11β-HSD2, which could lead to reduced levels of cortisol and more extensively cortisone. Aim The aim of this work is to investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in diurnal urine (dU) and blood samples. Methods This study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1628 pregnant women had serum (S) concentrations of 5 PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], and perfluorodecanoic acid (PFDA)) measured in the first trimester (median gestational week, GW 11). dU cortisol and cortisone (n = 344) and S-cortisol (n = 1048) were measured in the third trimester (median GW 27). Results In multiple regression analyses, a 2-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β = –9.1%, P Conclusion Early pregnancy maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2.

Antibiotic prophylaxis is a key element in prevention of surgical site infections. For the majority of orthopedic procedures, antibiotic administration follows fixed dosing regimens irrespective of weight. However, this may result in insufficient antibiotic target tissue concentrations and higher risk of surgical site infections in obese individuals. The aim of this study was to investigate the effect of weight-based cefuroxime dosing on plasma and target tissue concentrations. Eighteen female pigs were allocated into three groups differentiated by weight: 53–57 kg, 73–77 kg, and 93–97 kg. Microdialysis catheters were placed for continuous sampling in bone, muscle, and subcutaneous tissue during an 8h sampling interval. Blood samples were collected as reference. Cefuroxime was administered intravenously as a bolus according to weight (20 mg/kg). The primary endpoint was the time above the cefuroxime minimal inhibitory concentration for Staphylococcus aureus (T > MIC (4 μg/mL)). Comparable target tissue T > MICs (4 μg/mL) were found between weight groups. Mean T > MIC ranged between 116–137 min for plasma, 118–154 min for bone, 109–146 min for the skeletal muscle, and 117–165 min for subcutaneous tissue across the groups. Weight-based cefuroxime (20 mg/kg) dosing approach provides comparable perioperative plasma and target tissue T > MIC (4 μg/mL) in animals between 50–100 kg body weight, and thus a comparable prophylaxis of surgical site infections.

Aims This study aimed to investigate the potential of different markers to identify adequate stressing in subjects with and without caffeine intake prior to Rubidium-82 myocardial imaging. Methods and Results This study comprised 40 healthy subjects who underwent four serial Rubidium-82 rest/adenosine stress MPI; two with 0mg caffeine consumption (baseline MPIs) and two with controlled consumption of caffeine (arm 1: 100 and 300mg, or arm 2: 200 and 400mg). We report the sensitivity and specificity of seven markers ability to predict adequate adenosine-induced hyperemic response: (1) the splenic response ratio (SRR); (2) splenic stress-to-rest intensity ratios (SIR); (3) changes in heart rate (ΔHR); (4) percentwise change in heart rate (Δ%HR); (5) changes in the rate pressure product (ΔRPP); (6) changes in the systolic blood pressure (ΔSBP); and (7) changes in the cardiovascular resistance (ΔCVR). Adequate stressing was determined as stress myocardial blood flow > 3ml/g/min and a corresponding myocardial flow reserve >68% of the individual maximum myocardial flow reserve obtained in the baseline MPIs. Results 129 MPI sessions (obtained in 39 subjects) were considered for this study. The following sensitivities were obtained: SSR = 72.7%, SIR = 63.6%, ΔHR = 45.5%, Δ%HR = 77.3%, ΔRPP = 54.5%, ΔSBP = 47.7%, and ΔCVR =40.9%, while the specificities were SSR = 80.9%, SIR = 85.0%, ΔHR = 90.4%, Δ%HR = 81.6%, ΔRPP=81.1%, ΔSBP = 86.4%, and ΔCVR =90.4%. Conclusion The image-derived and physiological markers all provide acceptable sensitivities and specificities when patients follow the caffeine pausation before MPI. However, their use warrants great care when caffeine consumption cannot be ruled out.

INTRODUCTION: Surgical instrumentation in children with adolescent idiopathic scoliosis (AIS) is performed early in life and the implants are left in situ for the rest of the patient's life. Concern has been raised regarding persistent elevated levels of serum metal ions, but only a few studies on the topic have been published. The aim of this study was to compare the levels of serum metal ions in patients with AIS treated with either Harrington rod instrumentation or bracing.MATERIALS AND METHODS: AIS patients treated with Boston brace (BB) or posterior spinal fusion with Harrington rod instrumentation (HR) from 1983 to 1990 were requested to return to clinic. One hundred fifty-nine (73%) of 219 patients were available for follow-up of whom 115 agreed to have a blood draw.RESULTS: The proportion of patients who agreed to have a blood draw were similar in the BB (48 of 100, 48%) and HR (67 of 115, 60%, p = 0.085) groups. None of the surgical patients had their implants removed; mean age at follow-up (BB: 43.2 years vs HR: 43.5 years, p = 0.566) and mean length of follow-up (BB: 26.5 years vs HR: 24.5 years). Mean chromium serum levels were similar between the BB (2.7 nmol/L) and the HR (2.9 nmol/L, p = 0.827). Mean Cobalt serum levels were also similar between the BB (2.6 nmol/L) and the HR (2.8 nmol/L, p = 0.200).CONCLUSION: Serum metal ions were similar in AIS patients treated with bracing or Harrington rod instrumentation 25 years after initiation of treatment.

STUDY QUESTIONAre higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)?SUMMARY ANSWERAGD was similar in 3-month-old children born of mothers with PCOS compared to controls.WHAT IS KNOWN ALREADYAGD is considered a marker of prenatal androgenization.STUDY DESIGN, SIZE, DURATIONMaternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (MAIN RESULTS AND THE ROLE OF CHANCEAGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P LIMITATIONS, REASONS FOR CAUTIONThe diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities.WIDER IMPLICATIONS OF THE FINDINGSOur finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain.STUDY FUNDING/COMPETING INTEREST(S)Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported.

Caffeine consumption before adenosine stress myocardial perfusion imaging (MPI) is known to affect the hemodynamic response and, thus, reduce the stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) assessments. However, it is not clear if any sex-specific differences in the hemodynamic response after caffeine consumption exist. This study aimed to evaluate if such differences exist and, if so, their impact on MBF and MFR assessments. Methods: This study comprised 40 healthy volunteers (19 women). All volunteers underwent 4 serial rest/stress MPI sessions using 82Rb; 2 sessions were acquired without controlled caffeine consumption, and 2 sessions after oral ingestion of either 100 and 300 mg of caffeine or 200 and 400 mg of caffeine. For the caffeine imaging sessions, caffeine was ingested orally 1 h before the MPI scan. Results: Increase in plasma caffeine concentration (PCC) (mg/L) after consumption of caffeine was larger in women (MPI session without caffeine vs. MPI session with caffeine: women = 0.3 ± 0.2 vs. 5.4 ± 5.1, men = 0.1 ± 0.2 vs. 2.7 ± 2.6, both P < 0.001). Caffeine consumption led to reduced stress MBF and MFR assessments for men whereas no changes were reported for women (women [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 3.3 ± 0.6 vs. 3.0 ± 0.8 mL/g/min, P = 0.07; MFR = 3.7 ± 0.6 vs. 3.5 ± 1.0, P = 0.35; men [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 2.7 ± 0.7 vs. 2.1 ± 1.0 mL/g/min, P = 0.005; MFR = 3.8 ± 1.0 vs. 3.1 ± 1.4, P = 0.018). Significant differences in the stress MBF were observed for the 2 sexes (both P ≤ 0.001), whereas similar MFR was reported (both P ≥ 0.12). Conclusion: Associations between increases in PCC and reductions in stress MBF and MFR were observed for men, whereas women did not have the same hemodynamic response. Stress MBF was affected at lower PCCs in men than women.

The authors would like to apoligise for an error in one of the names listed in the author byline. Tina Kold Nieilsen should be Tina Kold Jensen, as above. The electronic version of this article has been updated at http://doi.org/10.1093/humrep/dez122. The authors would like to assure readers that this does not affect any content of the article.

The catecholamines, epinephrine (E) and norepinephrine (NE) are important both as neurotransmitters and hormones, and measurement of E and NE in plasma is therefore of great interest in medical research. However, the low concentrations of E and NE in plasma require an analysis method that is both specific and sensitive. Plasma sample E and NE were extracted using solid phase extraction, and analyzed by an in-sample ion-pairing chromatography (IPC) LC-MS/MS method, that enables the ion-pairing reagent to be diverted to waste without entering the ion source of the mass spectrometer. The method was validated with good performance characteristics and the limit of quantification (LOQ) was found to be 0.20 and 0.02 nmol/L for NE and E, respectively. In conclusion, this work presents development and validation of a method for determining E and NE in plasma with a measuring range covering the entire reference interval for human plasma.

Background A growing body of evidence suggests that vitamin K has beneficial effects on human health, especially cardiovascular and bone health. Vitamin K1 (phylloquinone), the predominant form of vitamin K in blood, is regarded as an indicator of vitamin K status, but to our knowledge no reference intervals (RIs) have been established for vitamin K1. Methods In this population-based study, vitamin K1 was measured in serum from 3808 Caucasian individuals without diabetes from 26 to 78 years of age. The need for gender- and age-partitioned vitamin K1 reference intervals was evaluated using Lahti’s method, and exclusion criteria were defined to obtain as healthy a study group as possible. The excluded subgroups were tested for differences in mean serum vitamin K1 levels. Serum vitamin K1 levels were quantified using an in-house newly developed, validated, and highly sensitive online SPE-LC-MS/MS method with a limit of quantitation of (LOQ) 0.05 nmol/L. Results The reference interval for serum vitamin K1 was 0.22 to 3.95 nmol/L for individuals aged 26 to 44 years and 0.35 to 3.70 nmol/L for individuals aged 45 to 78. Similar age-specific reference intervals were established for vitamin K1-triglyceride ratio being 0.20 to 3.16 and 0.31 to 3.44, respectively. No significant difference was found between genders. Serum vitamin K1 was detectable in all serum samples. Individuals with known comorbidity were found to have significantly lower serum vitamin K1 compared to those without comorbidity. Current smokers had lower serum vitamin K1 compared to nonsmokers. Conclusion Age-dependent reference intervals were established for serum vitamin K1 and vitamin K1-triglyceride ratio in a well-defined, healthy Caucasian population. Lower serum vitamin K1 levels were found in individuals with known comorbidity, suggesting an association between serum vitamin K1 and disease status. Further studies are needed to determine an optimal serum vitamin K1 level.

Caffeine is a nonselective competitive antagonist of the A2A-adenosine receptor that mediates coronary vasodilation [(1,2)][1]. However, the effect of interaction between caffeine and adenosine on myocardial blood flow is not clarified [(3)][2]. Therefore, we investigated whether caffeine changed