Prenatal exposure to airborne polychlorinated biphenyl congeners and male reproductive health.

STUDY QUESTION: Is fetal exposure to lower-chlorinated polychlorinated biphenyls (LC-PCBs) in indoor air of private homes built with PCB-containing materials associated with semen characteristics and testicular volume in adult men? SUMMARY ANSWER: We observed only marginal and inconsistent associations between maternal exposure to PCBs in indoor air and semen quality, testicular size and reproductive hormones in the adult offspring. WHAT IS KNOWN ALREADY: Recent studies have shown LC-PCBs to exhibit endocrine-disrupting properties and increase the risk of cryptorchidism. Although exposure to LC-PCBs in indoor air is relatively common, the long-term impact of prenatal exposure on male reproductive health has not yet been investigated. STUDY DESIGN, SIZE, DURATION: In this cohort study, participants were men (18+ years) whose mothers carried them while living in one of two residential areas where indoor air had been contaminated by LC-PCB evaporating from building materials in subsets of the apartments. Men were considered prenatally exposed if their mother had lived in a PCB-contaminated apartment and unexposed if their mother had lived in an uncontaminated apartment for a minimum of 1 year during the 3.6 years before conception or during the first trimester. Mothers of prenatally unexposed men could not have lived in a contaminated apartment at any point. Recruitment lasted from 2017 to 2019. In total, 73 exposed and 111 unexposed men gave a blood and semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Percentage differences in semen volume, sperm concentration, total sperm count, morphologically normal spermatozoa, progressively motile spermatozoa and DNA fragmentation index (DFI) between prenatally exposed and unexposed men were estimated using negative binomial regression. Associations with total and calculated free testosterone (CFT), LH and FSH were modeled using the linear regression. Odds of small testicular volume was estimated with logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the results of this study were conflicting. No differences in semen volume, sperm concentration, testosterone and CFT were observed between the groups, but there were slight indications of lower total sperm count, increased FSH and risk of small testicles, alongside lower sperm DFI and a higher proportion of normal spermatozoa in men exposed to LCB-PCBs from indoor air during fetal life. There is no apparent biologically plausible explanation for the apparently improved measures of DNA fragmentation and morphology, and these findings may have occurred purely by chance. LIMITATIONS, REASONS FOR CAUTION: Owing to the indirect measure of exposure, lack of adjustment for paternal factors, the potential for self-selection due to known exposure status and fertility issues, inability to take time spent away from the residence, limited statistical power and lack of comparable literature, independent replication of the study in larger cohorts is warranted. WIDER IMPLICATIONS OF THE FINDINGS: While our findings may appear reassuring for the large number of people residing and/or working in buildings with indoor air contaminated with LC-PCBs, further efforts to understand the full range of health consequences of fetal LC-PCB exposure are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Independent Research Fund Denmark (ref no. 6110-00085B), Bispebjerg Hospital, Landsbyggefonden, Realdania (ref. no. PRJ-2017-00176), Grundejernes Investeringsfond (ref. no. 18-58) and Helsefonden (ref. no. 16-B-01-22 and 21-B-0412). K.S.H. was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government. The authors declare that they have no financial, personal or professional competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Internalization, reduced growth, and behavioral effects following exposure to micro and nano tire particles in two estuarine indicator species.

Synthetic rubber emissions from automobile tires are common in aquatic ecosystems. To assess potential impacts on exposed organisms, early life stages of the estuarine indicator species Inland Silverside (Menidia beryllina) and mysid shrimp (Americamysis bahia) were exposed to three tire particle (TP) concentrations at micro and nano size fractions (0.0038, 0.0378 and 3.778 mg/L in mass concentrations for micro size particles), and separately to leachate, across a 5-25 PSU salinity gradient. Following exposure, M. beryllina and A. bahia had significantly altered swimming behaviors, such as increased freezing, changes in positioning, and total distance moved, which could lead to an increased risk of predation and foraging challenges in the wild. Growth for both A. bahia and M. beryllina was reduced in a concentration-dependent manner when exposed to micro-TP, whereas M. beryllina also demonstrated reduced growth when exposed to nano-TP (except lowest concentration). TP internalization was dependent on the exposure salinity in both taxa. The presence of adverse effects in M. beryllina and A. bahia indicate that even at current environmental levels of tire-related pollution, which are expected to continue to increase, aquatic ecosystems may be experiencing negative impacts.

Pre-validation of SENS-IS assay for in vitro skin sensitization of medical devices.

According to ISO 10993-1:2018, the skin sensitization potential of all medical devices must be evaluated, and for this endpoint ISO 10993-10:2010 recommends the use of in vivo assays. The goal of the present study was to determine if the in vitro SENS-IS assay could be a suitable alternative to the current in vivo assays. The SENS-IS assay uses the Episkin Large and SkinEthic RHE reconstructed human epidermis models to evaluate marker genes. In our study, the SENS-IS assay correctly identified 13 sensitizers spiked in a non-polar solvent. In a subsequent analysis six medical device silicone samples previously impregnated with sensitizers were extracted with polar and non-polar solvents. The SENS-IS assay correctly identified five of these extracts, while a sixth extract, which contained the weak sensitizer phenyl benzoate, was classified as negative. However, when this extract was concentrated, or a longer exposure time was used, the assay was able to detect phenyl benzoate. The SENS-IS assay was transferred to a naïve laboratory which correctly identified sensitizers in six blinded silicone samples, including the one containing phenyl benzoate. In light of these results, we conclude that the SENS-IS assay is able to correctly identify the presence of sensitizers in medical devices extracts.

A Comparison of Urine Dilution Ability between Adult Dominant Polycystic Kidney Disease, Other Chronic Kidney Diseases, and Healthy Control Subjects: A Case-Control Study.

The final dilution of urine is regulated via aquaporin-2 water channels in the distal part of the nephron. It is unclear whether urine dilution ability in autosomal dominant polycystic kidney disease patients (ADPKD patients) differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine dilution ability in ADPKD patients compared to non-ADPKD patients and healthy controls. Methods. Eighteen ADPKD, 16 non-ADPKD patients (both with chronic kidney disease, stage I-IV), and 18 healthy controls received an oral water load of 20 ml/kg body weight. Urine was collected in 7 consecutive periods. We measured free water clearance (CH2O), urine osmolality, urine output, fractional excretion of sodium, urine aquaporin2 (u-AQP2), and urine epithelial sodium channel (u-ENaC). Blood samples were drawn four times (at baseline, 2 h, 4 h, and 6 hours after the water load) for analyses of plasma osmolality, vasopressin, renin, angiotensin II, and aldosterone. Brachial and central blood pressure was measured regularly during the test. Results. The three groups were age and gender matched, and the patient groups had similar renal function. One hour after water load, the ADPKD patients had an increased CH2O compared to non-ADPKD patients (2.97 ± 2.42 ml/min in ADPKD patients vs. 1.31 ± 1.50 ml/min in non-ADPKD patients, p0.029). The reduction in u-AQP2 and u-ENaC occurred earlier in ADPKD than in non-ADPKD patients. Plasma concentrations of vasopressin, renin, angiotensin II, and aldosterone and blood pressure measurements did not show any differences that could explain the deviation in urine dilution capacity between the patient groups. Conclusions. ADPKD patients had a higher CH2O than non-ADPKD patients after an oral water load, and u-AQP2 and u-ENaC were more rapidly reduced than in non-ADPKD patients. Thus, urine-diluting capacity may be better preserved in ADPKD patients than in non-ADPKD patients.

Urine concentration ability is reduced to the same degree in adult dominant polycystic kidney disease compared with other chronic kidney diseases in the same CKD-stage and lower THAN in healthy control subjects - a CASE control study.

BACKGROUND: Concentration of the urine is primarily regulated via vasopressin dependent aquaporin-2 water channels in the apical membrane of kidney principal cells. It is unclear whether urine concentration ability in ADPKD differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine concentration ability in ADPKD patients compared to non-ADPKD patients and healthy controls. METHODS: A seventeen hour long water deprivation test was carried out in 17 ADPKD patients (CKD I-IV), 16 non-ADPKD patients (CKD I-IV), and 18 healthy controls. Urine was collected in 4 consecutive periods during water deprivation (12 h, 1 h, 2 h and 2 h, respectively) and analyzed for osmolality (u-Osm), output (UO), fractional excretion of sodium (FENa), aquaporin2 (u-AQP2) and ENaC (u-ENaC). Blood samples were drawn trice (after 13-, 15-, and 17 h after water deprivation) for analyses of osmolality (p-Osm), vasopressin (p-AVP), and aldosterone (p-Aldo). RESULTS: U-Osm was significantly lower and FENa significantly higher in both ADPKD patients and non-ADPKD patients compared to healthy controls during the last three periods of water deprivation. During the same periods, UO was higher and secretion rates of u-AQP2 and u-ENaC were lower and at the same level in the two groups of patients compared to controls. P-AVP and p-Osm did not differ significantly between the three groups. P-Aldo was higher in both groups of patients than in controls. CONCLUSIONS: Urine concentration ability was reduced to the same extent in patients with ADPKD and other chronic kidney diseases with the same level of renal function compared to healthy controls. The lower urine excretion of AQP2 and ENaC suggests that the underlying mechanism may be a reduced tubular response to vasopressin and aldosterone. TRIAL REGISTRATION: Current Controlled Trial NCT04363554 , date of registration: 20.08.2017.

Circulating trimethyllysine and risk of acute myocardial infarction in patients with suspected stable coronary heart disease.

BACKGROUND: The carnitine precursor trimethyllysine (TML) is associated with progression of atherosclerosis, possibly through a relationship with trimethylamine-N-oxide (TMAO). Riboflavin is a cofactor in TMAO synthesis. We examined prospective relationships of circulating TML and TMAO with acute myocardial infarction (AMI) and potential effect modifications by riboflavin status. METHODS: By Cox modelling, risk associations were examined amongst 4098 patients (71.8% men) with suspected stable angina pectoris. Subgroup analyses were performed according to median plasma riboflavin. RESULTS: During a median follow-up of 4.9 years, 336 (8.2%) patients experienced an AMI. The age- and sex-adjusted hazard ratio (HR) (95% CI) comparing the 4th vs. 1st TML quartile was 2.19 (1.56-3.09). Multivariable adjustment for traditional cardiovascular risk factors and indices of renal function only slightly attenuated the risk estimates [HR (95% CI) 1.79 (1.23-2.59)], which were particularly strong amongst patients with riboflavin levels above the median (Pint  = 0.035). Plasma TML and TMAO were strongly correlated (rs  = 0.41; P < 0.001); however, plasma TMAO was not associated with AMI risk in adjusted analyses [HR (95% CI) 0.81 (0.58-1.14)]. No interaction between TML and TMAO was observed. CONCLUSION: Amongst patients with suspected stable angina pectoris, plasma TML, but not TMAO, independently predicted risk of AMI. Our results motivate further research on metabolic processes determining TML levels and their potential associations with cardiovascular disease. We did not adjust for multiple comparisons, and the subgroup analyses should be interpreted with caution.

Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects - a randomized controlled trial.

BACKGROUND: Chloride is speculated to have nephrotoxic properties. In healthy subjects we tested the hypothesis that acute chloride loading with 3% saline would induce kidney injury, which could be prevented with the loop-diuretic furosemide. METHODS: The study was designed as a randomized, placebo-controlled, crossover study. Subjects were given 3% saline accompanied by either placebo or furosemide. Before, during and after infusion of 3% saline we measured glomerular filtration rate (GFR), fractional excretion of sodium (FENa), urinary chloride excretion (u-Cl), urinary excretions of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ), neutrophil gelatinase-associated lipocalin (u-NGAL) and kidney injury molecule-1 (u-KIM-1) as marker of kidney injury and vasoactive hormones: renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and arginine vasopressin (p-AVP). Four days prior to each of the two examinations subjects were given a standardized fluid and diet intake. RESULTS: After 3% saline infusion u-NGAL and KIM-1 excretion increased slightly (u-NGAL: 17 ± 24 during placebo vs. -7 ± 23 ng/min during furosemide, p = 0.039, u-KIM-1: 0.21 ± 0.23 vs - 0.06 ± 0.14 ng/ml, p <  0.001). The increase in u-NGAL was absent when furosemide was given simultaneously, and the responses in u-NGAL were not significantly different from placebo control. Furosemide changed responses in u-KIM-1 where a delayed increase was observed. GFR was increased by 3% saline but decreased when furosemide accompanied the infusion. U-Na, FENa, u-Cl, and u-osmolality increased in response to saline, and the increase was markedly pronounced when furosemide was added. FEK decreased slightly during 3% saline infusion, but simultaneously furosemide increased FEK. U-AQP2 increased after 3% saline and placebo, and the response was further increased by furosemide. U-ENaCγ decreased to the same extent after 3% saline infusion in the two groups. 3% saline significantly reduced PRC, p-AngII and p-Aldo, and responses were attenuated by furosemide. p-AVP was increased by 3% saline, with a larger increase during furosemide. CONCLUSION: This study shows minor increases in markers of kidney injury after 3% saline infusion Furosemide abolished the increase in NGAL and postponed the increase in u-KIM-1. The clinical importance of these findings needs further investigation. TRIAL REGISTRATION: (EU Clinical trials register number: 2015-002585-23 , registered on 5th November 2015).

Assessment of dose to functional sub-structures in the lower urinary tract in locally advanced cervical cancer radiotherapy.

PURPOSE: To provide an analysis of dose distribution in sub-structures that could be responsible for urinary toxicity after Image-Guided Adaptive BrachyTherapy (IGABT) in Locally Advanced Cervical Cancer (LACC). METHODS: 105 LACC patients treated with radiochemotherapy and IGABT were selected. Sub-structures (bladder wall, trigone, bladder neck, urethra) were contoured on IGABT-planning MRIs. D2cm3 and D0.1cm3, ICRU Bladder-Point (ICRU BP) and Posterior-Inferior Border of Symphysis points (PIBS, PIBS + 2 cm, PIBS - 2 cm) doses were extracted. Internal-Urethral-Ostium (IUO) and PIBS-Urethra (PIBS-U) points were defined as urethral dose surrogates. Finally, the Vaginal Reference Length (VRL) was extracted. Values were converted into total EBRT + BT equivalent dose in 2 Gy fractions using α/ß = 3 and T1/2 = 1.5 h. RESULTS: Median D2cm3 for bladder and trigone were 71.7[interquartile-range:66.5;74.1]Gy and 57.8[53.3;63.6]Gy, respectively, while median D0.1cm3 were 82.2[77.6;89.1]Gy and 70.7[62.0;76.7]Gy, respectively. Median ICRU BP dose was 63.7[56.5;70.5]Gy and correlated with trigone D2cm3 and D0.1cm3, while bladder and trigone D2cm3 had poor correlation (R2 = 0.492), as well as D0.1cm3 (R2 = 0.356). Bladder neck D0.1cm3 was always lower than trigone D0.1cm3 and higher than IUO. Correlation between PIBS + 2 cm and IUO was poor (R2 = 0.273), while PIBS and PIBS-U were almost equal (R2 = 0.990). VRL correlated with dose to bladder base. CONCLUSIONS: The study confirmed that ICRU BP and trigone doses correlate. Bladder D2cm3 is not representative of trigone dose because hotspots are often placed in the bladder dome. VRL is a good indicator for bladder base sparing. In addition to D2cm3 and D0.1cm3 for whole bladder, ICRU BP, trigone D2cm3 and D0.1cm3, IUO and PIBS are useful for lower urinary tract reporting.

Association of plasma neopterin with risk of an inpatient hospital diagnosis of atrial fibrillation: results from two prospective cohort studies.

BACKGROUND: Link between inflammation and atrial fibrillation (AF) has been increasingly recognized. Neopterin, a biomarker of cellular immune activation, may be associated with incident AF. OBJECTIVE: To investigate the association between plasma neopterin levels and risk of an inpatient hospital diagnosis of AF, and to evaluate a joint association of neopterin and a nonspecific inflammatory marker C-reactive protein (CRP) in two prospective cohorts. METHODS: We performed a prospective analysis from a community-based cohort (the Hordaland Health Study (HUSK), n = 6891), and validated the findings in a cohort of patients with suspected stable angina pectoris (the Western Norway Coronary Angiography Cohort (WECAC), n = 2022). RESULTS: In both cohorts, higher plasma levels of neopterin were associated with an increased risk of incident AF after adjustment for age, sex, body mass index, current smoking, diabetes, hypertension and renal function. The multivariable-adjusted hazard ratio (HR) (95% CI) per one SD increment of log-transformed neopterin was 1.20 (1.10-1.32) in HUSK and 1.26 (1.09-1.44) in WECAC. Additional adjustment for CRP did not materially affect the risk association for neopterin. The highest risk of AF was found among individuals with both neopterin and CRP levels above the median (HR: 1.54; 95% CI: 1.16-2.05 in HUSK and HR: 1.67; 95% CI: 1.11-2.52 in WECAC). CONCLUSIONS: Our findings indicate an association of plasma neopterin with risk of an inpatient hospital diagnosis of AF, which remains after adjustment for traditional risk factors as well as for CRP. This study highlights a role of cellular immune activation, in addition to inflammation, in AF pathogenesis.

Screening for late-onset Pompe disease in western Denmark.

OBJECTIVE: Late-onset Pompe disease (LOPD) is a rare autosomal recessively inherited metabolic myopathy caused by reduced activity of the lysosomal enzyme alpha-glucosidase. In a previous screening study at two large neuromuscular university clinics in Denmark, three patients with LOPD were identified out of 103 patients screened. No systematic screening has been performed at the other neurological departments in the western part of Denmark. Thus, patients with a diagnosis of unspecified myopathy were screened for LOPD. MATERIALS AND METHODS: At seven neurological departments in the western part of Denmark, medical records were evaluated for all patients registered with myopathy diagnosis codes (ICD 10 codes: G 71.0-71.9 and G 72.0-72.9) during the period January 1, 2002, to December 31, 2012. If no specific diagnosis has been reached, patients were invited for screening. Dried blood spot (DBS) test was used to analyze the activity of the enzyme alpha-glucosidase. RESULT: A total of 654 patients were identified. From the medical records, information was obtained concerning symptoms, family history, electromyography, muscle biopsy results and creatine kinase levels. Eighty-seven patients (13.3%) (males 61%) at a mean age of 53.3 years (SD 16.5) fulfilled the criteria for screening. A DBS test was performed in 47 (54%) patients. In all patients, the enzyme activity was within reference values. CONCLUSION: None of the screened patients had a reduced activity of the enzyme alpha-glucosidase. Although the cohort studied was small, our findings do not suggest that LOPD is underdiagnosed in patients with unspecified myopathy in western Denmark.

Criterion validity of the Physical Activity Scale (PAS2) in Danish adults.

BACKGROUND: The Physical Activity Scale (PAS2) was developed to measure physical activity (PA) during work, transportation and leisure time, in the Danish adult population. The objective of this study was to assess the criterion validity of PAS2 against a combined accelerometer and heart rate monitor in Danish adults and to investigate if the criterion validity differed by socio-demographic factors and body mass index. METHOD: A total of 330 Danish adults (mean age = 46.7 years, 38.5% men) participating in the Health2008 study completed the PAS2 questionnaire and wore a combined accelerometer and heart rate sensor for seven days. Average daily estimates from PAS2 were categorised into time spent in sedentary behaviour, light PA, moderate PA and vigorous PA and were compared to the objective measures. RESULTS: PAS2 accounted for 19.5 hours/day on average. Time spent in sedentary behaviour, light and moderate-intensity PA was weakly correlated with objective data (polychoric correlation coefficients (PCC): 0.18-0.20), whereas vigorous intensity PA was moderately correlated (PCC: 0.54, p = 0.04). Mean bias was -2.3 hours/day (95% limits of agreement (LoA): -9.04 to 4.34) for sedentary behaviour, 1.68 hours/day (LoA: 8.02 to -4.62) for light activity, 0.55 hours/day (LoA: 3.37 to -2.26) for moderate activity and 0.12 hours/day (LoA: 0.57 to 0.33) for vigorous activity. Criterion validity was lower in women, in participants who were above 40 years, overweight, had short education and were unemployed. CONCLUSIONS: PAS2 overestimated time spent on light, moderate and vigorous intensity PA and underestimated time spent on sedentary behaviour. Validity differed by key socio-demographic characteristics.

Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB.

Cellular movement is controlled by small GTPases, such as RhoA. Although migration is crucial for cancer cell invasion, the specific role of RhoA in tumor formation is unclear. Inducing skin tumors in mice with a keratinocyte-restricted loss of RhoA, we observed increased tumor frequency, growth and invasion. In vitro invasion assays revealed that in the absence of RhoA cell invasiveness is increased in a Rho-associated protein kinase (ROCK) activation and cell contraction-dependent manner. Surprisingly, loss of RhoA causes increased Rho signaling via overcompensation by RhoB because of reduced lysosomal degradation of RhoB in Gamma-aminobutyric acid receptor-associated protein (GABARAP)+ autophagosomes and endosomes. In the absence of RhoA, RhoB relocalized to the plasma membrane and functionally replaced RhoA with respect to invasion, clonogenic growth and survival. Our data demonstrate for the first time that RhoA is a tumor suppressor in 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate skin carcinogenesis and identify Rho signaling dependent on RhoA and RhoB as a potent driver of tumor progression.

Ultrasound-guided lumbar plexus block in volunteers; a randomized controlled trial.

Background: The currently best-established ultrasound-guided lumbar plexus block (LPB) techniques use a paravertebral location of the probe, such as the lumbar ultrasound trident (LUT). However, paravertebral ultrasound scanning can provide inadequate sonographic visibility of the lumbar plexus in some patients. The ultrasound-guided shamrock LPB technique allows real-time sonographic viewing of the lumbar plexus, various anatomical landmarks, advancement of the needle, and spread of local anaesthetic injectate in most patients. We aimed to compare block procedure outcomes, effectiveness, and safety of the shamrock vs LUT. Methods: Twenty healthy men underwent ultrasound-guided shamrock and LUT LPBs (2% lidocaine­adrenaline 20 ml, with 1 ml diluted contrast added) in a blinded randomized crossover study. The primary outcome was block procedure time. Secondary outcomes were procedural discomfort, number of needle insertions, injectate spread assessed with magnetic resonance imaging, sensorimotor effects, and lidocaine pharmacokinetics. Results: The shamrock LPB procedure was faster than LUT (238 [sd 74] vs 334 [156] s; P=0.009), more comfortable {numeric rating scale 0­10: 3 [interquartile range (IQR) 2­4] vs 4 [3­6]; P=0.03}, and required fewer needle insertions (2 [IQR 1­3] vs 6 [2­12]; P=0.003). Perineural injectate spread seen with magnetic resonance imaging was similar between the groups and consistent with motor and sensory mapping. Zero/20 (0%) and 1/19 (5%) subjects had epidural spread after shamrock and LUT (P=1.00), respectively. The lidocaine pharmacokinetics were similar between the groups. Conclusions: Shamrock was faster, more comfortable, and equally effective compared with LUT. Clinical trial registration: NCT02255591

Short-term telemedical home blood pressure monitoring does not improve blood pressure in uncomplicated hypertensive patients.

Telemonitoring of home blood pressure measurements (TBPM) is a new and promising supplement to diagnosis, control and treatment of hypertension. We wanted to compare the outcome of antihypertensive treatment based on TBPM and conventional monitoring of blood pressure. Participants were recruited from a prevalence study among citizens aged 55-64 years in the municipality of Holstebro, Denmark. The study was a randomized, controlled, unblinded 3 months' trial. In the intervention group, antihypertensive treatment was based on TBPM with transmission of the measurements and subsequent communication by telephone or e-mail. In the control group, patients received usual care. Primary outcome was reduction in daytime ambulatory blood pressure measurements (ABPM) from baseline to 3 months' follow-up. Of 375 participants randomized, primary outcome data were available for 356 (95%). In both groups, daytime ABPM decreased significantly. The decrease in daytime ABPM in the intervention group was systolic/diastolic, -8±12/-4±7 mm Hg. This did not differ significantly from the control group's -8±13/-4±8 mm Hg. An equal number of participants obtained normal daytime ABPM, in the intervention group 17% (31/175) versus control 21% (37/181), P=0.34. We found that both TBPM patients and controls achieved a significant blood pressure reduction in this randomized, controlled, unblinded 3-month trial. We found no difference in blood pressure reduction or number of patients reaching blood pressure goals. Further information and education of some general practitioners seem to be relevant regarding blood pressure management and control of hypertension.

Lipid-modified G4-decoy oligonucleotide anchored to nanoparticles: delivery and bioactivity in pancreatic cancer cells.

KRAS is mutated in >90% of pancreatic ductal adenocarcinomas. As its inactivation leads to tumour regression, mutant KRAS is considered an attractive target for anticancer drugs. In this study we report a new delivery strategy for a G4-decoy oligonucleotide that sequesters MAZ, a transcription factor essential for KRAS transcription. It is based on the use of palmitoyl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with lipid-modified G4-decoy oligonucleotides and a lipid-modified cell penetrating TAT peptide. The potency of the strategy in pancreatic cancer cells is demonstrated by cell cytometry, confocal microscopy, clonogenic and qRT-PCR assays.

Intra-individual variability in day-to-day and month-to-month measurements of physical activity and sedentary behaviour at work and in leisure-time among Danish adults.

BACKGROUND: Accelerometers can obtain precise measurements of movements during the day. However, the individual activity pattern varies from day-to-day and there is limited evidence on measurement days needed to obtain sufficient reliability. The aim of this study was to examine variability in accelerometer derived data on sedentary behaviour and physical activity at work and in leisure-time during week days among Danish office employees. METHODS: We included control participants (n = 135) from the Take a Stand! Intervention; a cluster randomized controlled trial conducted in 19 offices. Sitting time and physical activity were measured using an ActiGraph GT3X+ fixed on the thigh and data were processed using Acti4 software. Variability was examined for sitting time, standing time, steps and time spent in moderate-to-vigorous physical activity (MVPA) per day by multilevel mixed linear regression modelling. RESULTS: Results of this study showed that the number of days needed to obtain a reliability of 80% when measuring sitting time was 4.7 days for work and 5.5 days for leisure time. For physical activity at work, 4.0 days and 4.2 days were required to measure steps and MVPA, respectively. During leisure time, more monitoring time was needed to reliably estimate physical activity (6.8 days for steps and 5.8 days for MVPA). CONCLUSIONS: The number of measurement days needed to reliably estimate activity patterns was greater for leisure time than for work time. The domain specific variability is of great importance to researchers and health promotion workers planning to use objective measures of sedentary behaviour and physical activity. TRIAL REGISTRATION: Clinical trials NCT01996176 .

Displacement of popliteal sciatic nerve catheters after major foot and ankle surgery: a randomized controlled double-blinded magnetic resonance imaging study.

BACKGROUND: Popliteal sciatic nerve catheters (PSNCs) are associated with a high frequency of displacement. We aimed to estimate the frequency of catheter displacement after 48 h with magnetic resonance imaging (MRI) in patients with PSNCs after major foot and ankle surgery randomized to catheter insertion either with a short-axis in-plane (SAX-IP) approach perpendicular to the nerve or with a short-axis out-of-plane (SAX-OOP) approach parallel to the nerve. METHODS: Forty patients were randomly allocated to SAX-IP or SAX-OOP PSNC. Ropivacaine 0.75% 20 ml was injected via the catheter followed by ropivacaine 0.2% 10 ml h(-)1 infusion. Correct primary catheter placement was ensured after initial injection of local anaesthetic via the catheter. Forty-eight hours after insertion, MRI was performed after injection of saline with added contrast (Dotarem) via the catheter. The primary outcome was catheter displacement estimated as the frequency of spread of contrast exclusively outside the paraneurium. RESULTS: All patients had correct primary catheter placement. The frequency of displacement 48 h after insertion of the PSNC was 40% when inserted perpendicular to the nerve vs 10% parallel to the nerve (difference was 30 percentage points, 95% CI: 3-53 percentage points). The relative risk of displacement was four times larger (95% CI: 0.8-10, P<0.028) in the SAX-IP vs the SAX-OOP group. The morphine consumption was 150% greater in the SAX-IP compared with the SAX-OOP group. CONCLUSION: Popliteal sciatic nerve catheters for major foot and ankle surgery inserted with ultrasound guidance parallel to the sciatic nerve have a significantly lower frequency of displacement compared with those inserted perpendicular to the nerve. CLINICAL TRIAL REGISTRATION: NCT02200016.

B vitamin treatments modify the risk of myocardial infarction associated with a MTHFD1 polymorphism in patients with stable angina pectoris.

BACKGROUND: Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease. METHODS AND RESULTS: We explored the association between a MTHFD1 polymorphism (rs1076991 C > T) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n = 2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23-1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01-2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55-3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86-1.93) or folic acid/B12 (1.17; 95% CI, 0.83-1.65). CONCLUSION: A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors.

Improving organic tandem solar cells based on water-processed nanoparticles by quantitative 3D nanoimaging.

Organic solar cells have great potential for upscaling due to roll-to-roll processing and a low energy payback time, making them an attractive sustainable energy source for the future. Active layers coated with water-dispersible Landfester particles enable greater control of the layer formation and easier access to the printing industry, which has reduced the use of organic solvents since the 1980s. Through ptychographic X-ray computed tomography (PXCT), we image quantitatively a roll-to-roll coated photovoltaic tandem stack consisting of one bulk heterojunction active layer and one Landfester particle active layer. We extract the layered morphology with structural and density information including the porosity present in the various layers and the silver electrode with high resolution in 3D. The Landfester particle layer is found to have an undesired morphology with negatively correlated top- and bottom interfaces, wide thickness distribution and only partial surface coverage causing electric short circuits through the layer. By top coating a polymer material onto the Landfester nanoparticles we eliminate the structural defects of the layer such as porosity and roughness, and achieve the increased performance larger than 1 V expected for a tandem cell. This study highlights that quantitative imaging of weakly scattering stacked layers of organic materials has become feasible by PXCT, and that this information cannot be obtained by other methods. In the present study, this technique specifically reveals the need to improve the coatability and layer formation of Landfester nanoparticles, thus allowing improved solar cells to be produced.

High pulse pressure is not associated with abnormal activation of the renin-angiotensin-aldosterone system in repaired aortic coarctation.

We investigated the relationship between pulse pressure (PP)--a surrogate marker of arterial stiffness-and activity of the renin-angiotensin-aldosterone system (RAAS) in adult patients with repaired coarctation and normal left ventricular (LV) function. A total of 114 patients (44 (26-74) years, 13 (0.1-40) years at repair) and 20 healthy controls were examined with 24-h ambulatory blood pressure monitoring, echocardiography, vasoactive hormone levels and magnetic resonance of the thoracic aorta. Forty-one patients (36%) were taking antihypertensives (28 RAAS inhibitors). Fifty-one had mean 24-h blood pressures >130/80 mm Hg. Hypertension was not associated with age at repair (P=0.257). Patients had higher PP and LV mass compared with controls (52±11 vs. 45±5 mm Hg and 221±71 vs. 154±55 g, respectively; both P<0.05). Differences were more pronounced in the presence of recoarctation, but independently of RAA levels. Even normotensive patients had higher LV mass than controls. LV mass and recoarctation were correlated with PP levels. In conclusion, adult patients with repaired coarctation have increased PP and LV mass compared with controls. PP increased with increasing recoarctation. Hypertension was present also in the absence of recoarctation. These changes could not be explained by abnormal activation of the RAAS.