Candidate genetic variants and antidepressant-related fall risk in middle-aged and older adults.

BACKGROUND: Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users. METHODS: The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated. RESULTS: In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00). CONCLUSION: This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.

A Propensity Score Matched Approach to Assess the Associations of Commonly Prescribed Medications with Fall Risk in a Large Harmonized Cohort of Older Ambulatory Persons.

INTRODUCTION: Several medication classes are considered to present risk factors for falls. However, the evidence is mainly based on observational studies that often lack adequate adjustment for confounders. Therefore, we aimed to assess the associations of medication classes with fall risk by carefully selecting confounders and by applying propensity score matching (PSM). METHODS: Data from several European cohorts, harmonized into the ADFICE_IT cohort, was used. Our primary outcome was time until the first fall within 1-year follow-up. The secondary outcome was a fall in the past year. Our exposure variables were commonly prescribed medications. We used 1:1 PSM to match the participants with reported intake of specific medication classes with participants without. We constructed Cox regression models stratified by the pairs matched on the propensity score for our primary outcome and conditional logistic regression models for our secondary outcome. RESULTS: In total, 32.6% of participants fell in the 1-year follow-up and 24.4% reported falling in the past year. ACE inhibitor users (prevalence of use 15.3%) had a lower fall risk during follow-up when matched to non-users, with a hazard ratio (HR) of 0.82 (95% CI 0.68-0.98). Also, statin users (prevalence of use 20.1%) had a lower risk, with an HR of 0.76 (95% CI 0.65-0.90). Other medication classes showed no association with risk of first fall. Also, in our secondary outcome analyses, statin users had a significantly lower risk. Furthermore, ß-blocker users had a lower fall risk and proton pump inhibitor use was associated with a higher risk in our secondary outcome analysis. CONCLUSION: Many commonly prescribed medication classes showed no associations with fall risk in a relatively healthy population of community-dwelling older persons. However, the treatment effects and risks can be heterogeneous between individuals. Therefore, focusing on identification of individuals at risk is warranted to optimize personalized falls prevention.

Exploring diastolic pressure ratio to fractional flow reserve discordance and a hypothesis on tailoring diastolic pressure ratio cut-off values to improve diagnostic accuracy in the mid- and distal-LAD.

Previous studies have identified a higher rate of discordance between non-hyperaemic pressure ratios and FFR in the LAD when compared to the other two coronary arteries. We hypothesised that in keeping with recently published data, we would identify a higher discordance rate between diastolic pressure ratio (DPR) and FFR in the LAD compared to the RCA or LCx. In our study, 12.7% of LAD lesions had discordant results compared with 2.4% of non-LAD lesions. This represents a statistically significant increased rate of discordance in LAD lesions compared to non-LAD lesions (p = 0.04986). Note was made of a tendency for non-proximal LAD lesions to be associated with false-positive DPR results in the borderline range (0.88 and 0.89). In a speculative, hypothesis generating post-hoc analysis, we found an improved diagnostic accuracy of DPR when the cut-off value for a positive DPR in the non-proximal LAD was changed to ≤0.87. It is fathomable that improvements in the diagnostic accuracy of DPR for FFR may be improved by tailoring DPR cut-offs to the location of the lesion assessed.

Enzymatic outside-in cross-linking enables single-step microcapsule production for high-throughput three-dimensional cell microaggregate formation.

Cell-laden hydrogel microcapsules enable the high-throughput production of cell aggregates, which are relevant for three-dimensional tissue engineering and drug screening applications. However, current microcapsule production strategies are limited by their throughput, multistep protocols, and limited amount of compatible biomaterials. We here present a single-step process for the controlled microfluidic production of single-core microcapsules using enzymatic outside-in cross-linking of tyramine-conjugated polymers. It was hypothesized that a physically, instead of the conventionally explored biochemically, controlled enzymatic cross-linking process would improve the reproducibility, operational window, and throughput of shell formation. Droplets were flown through a silicone delay line, which allowed for highly controlled diffusion of the enzymatic cross-linking initiator. The microcapsules' cross-linking density and shell thickness is strictly depended on the droplet's retention time in the delay line, which is predictably controlled by flow rate. The here presented hydrogel cross-linking method allows for facile and cytocompatible production of cell-laden microcapsules compatible with the formation and biorthogonal isolation of long-term viable cellular spheroids for tissue engineering and drug screening applications.

Applications of cardiac computed tomography in electrophysiology intervention.

Cardiac electrophysiology is an evolving specialty that has seen rapid advances in recent years. Concurrently, there has been much progress in the field of cardiac imaging. Electrophysiologists are increasingly requesting cross-sectional imaging in advance of many procedures. Pulmonary vein isolation and left atrial appendage (LAA) occlusion are now an established treatment options for atrial fibrillation. In patients undergoing pulmonary vein isolation, applications of computed tomography (CT) include evaluating the left atrial and pulmonary venous anatomy, excluding LAA thrombus and assessing for pulmonary vein stenosis. In those undergoing LAA occlusion, CT may be of value in assessing the size, position, and morphology of the LAA as well as for determining correct positioning of the device and evaluating for peri-device leak. Implantable cardiac devices are now commonly used in the management of cardiac failure and cardiac arrhythmias. Applications of CT prior to device implantation include detecting myocardial scar, evaluating for mechanical dyssynchrony as well as visualising the coronary venous anatomy.

Former male elite athletes have better metabolic health in late life than their controls.

Elite-class athletes have longer life expectancy and lower risk for chronic noncommunicable diseases possibly because of physically active and healthier lifestyle. In this study, we assessed former male Finnish elite-class athletes' (n = 392) and their matched controls' (n = 207) body composition, and risk for the metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) in later life. Compared with the controls, the former athletes had lower body fat percentage (24.8% vs 26.0%, P = 0.021), lower risk for MS [odds ratio (OR) 0.57, 95% confidence interval (CI) 0.40-0.81], and NAFLD (OR 0.61, 95% CI 0.42-0.88). High volume of current leisure-time physical activity (LTPA) was associated with lower body fat percentage (P for trend < 0.001). When current volume of LTPA increased 1 MET h/week, the risk of MS and NAFLD decreased (OR 0.99, 95% CI 0.98-0.99 and OR 0.97, 95% CI 0.96-0.98, respectively). Although a career as an elite-class athlete during young adulthood may help to protect from developing metabolic syndrome, present exercise levels and volume of LTPA seem equally important as well.

Hypoglycaemic symptoms and hypoglycaemia threshold in older people with diabetes--a patient perspective.

OBJECTIVES: To investigate patients' views about their lowest tolerable blood glucose level and explore symptoms they may develop below that level. DESIGN: A semi-structured patient interview. SETTING: Outpatient clinic for older people (≥75 years) with diabetes. PARTICIPANTS: Patients attending an outpatient clinic over a six months period who are monitoring their blood glucose at home and able to participate in interview. RESULTS: Sixty one patients gave answers to the interview questions. Mean (SD) age was 82.3 (3.9) years and 33 (54%) were females. All patients indicated that they were usually aware when hypoglycaemia occurs but the symptoms reported were mostly non specific. The threshold for hypoglycaemia was 5 mmol/L in 13 (21%) patients, 6 mmol/L in 14 (23%) patients, 7 mmol/L in 13 (21%) patients, 8 mmol/L in 17 (28%) patients and 9 mmol/L in 4 (7%) patients. There was no significant difference between patients who were symptomatic at a higher blood glucose level (>6 mmo/L) and those who developed symptoms at a lower level (≤6 mmol/L). CONCLUSION: Older people with diabetes who seem to be aware of hypoglycaemia report mostly non specific symptoms. The threshold of experiencing hypoglycaemic symptoms appears to be higher than the usually defined <4 mmol/L.

Esophageal tolerance to high-dose stereotactic ablative radiotherapy.

Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

SU-E-J-177: Characterization of the Effect of 'Lung Detail' CT Reconstruction Algorithm on Radiation Therapy Dose Calculation.

PURPOSE: Precise tumor delineation is important in thoracic radiation therapy planning, and using a 'lung detail' computed tomography (CT) reconstruction algorithm can assist in visualizing the tumor. We seek to determine the dosimetric impact of utilizing a lung detail algorithm versus a standard algorithm on calculated dose in radiation treatment planning. METHODS: Ten patients, with 12 tumors, were analyzed in this study. Two CT scans, one reconstructed using a standard algorithm and one using a lung detail algorithm, were generated for each of 12 lung tumors. Treatment plans were calculated for each CT scan, with 7 tumors receiving stereotactic ablative radiotherapy (SABR) and 5 receiving intensity-modulated radiation therapy (IMRT). The Hounsfield unit (HU) and dose values for each voxel of the planning tumor volume (PTV), esophagus, spinal cord, and contralateral lung in both the CT and dose images were exported to MATLAB. For each contour, the voxel-by-voxel differences in the HU and dose distributions between the two scans were analyzed along with dose-volume histogram (DVH) data. RESULTS: Despite changes in HU values, the voxel-by-voxel analysis showed a negligible shift in dose values. The mean differences in dose for PTV, esophagus, spinal cord, and contralateral lung ranged from -12.12 to 22.57, -2.21 to 7.40, -0.50 to 5.93, and -1.12 to 7.41 cGy, respectively. DVH comparisons demonstrated no meaningful difference between plans. The mean PTV, esophagus, spinal cord, and contralateral lung doses measured from the DVH shifted between plans an average of 3.5, 2.93, -0.6 and -0.35 cGy, respectively. These dose differences are all less than 1% of the dose prescribed to the tumor and are not measurable by current technology. CONCLUSIONS: The lung detail reconstruction algorithm, when applied to thoracic radiation treatment planning CT scans, can help precisely delineate tumor with negligible dosimetric impact.

SU-D-BRB-01: 4D-CT Lung Ventilation Images Vary with 4D-CT Sorting Techniques.

PURPOSE: 4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques. METHODS: Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared. RESULTS: In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.79±0.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase. CONCLUSIONS: 4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

On-treatment function testing of platelets and long-term outcome of patients with peripheral arterial disease undergoing transluminal angioplasty.

OBJECTIVE: To assess the clinical importance of on-treatment function testing of platelets in patients on aspirin after catheter-based vascular interventions. MATERIALS AND METHODS: In 109 patients with symptomatic peripheral arterial disease (PAD) of the lower limbs, platelet function testing (adenosine diphosphate-, collagen- and epinephrine-induced aggregation using light transmission aggregometry) was performed before and at multiple time points up to 1 year after a percutaneous angioplasty. Using univariate mixture models and Box-Cox transformation to ensure normally distributed individual variances, we investigated if an intraindividual variability exists and if it has a consequence for clinical outcome. RESULTS: Response to aspirin as measured by platelet aggregometry varies considerably over time in most patients. However, the intraindividual variance over time was not significantly correlated either with restenosis/reocclusion after 1 year or with adverse long-term outcome (occurrence of death for cardiovascular cause, stroke or myocardial infarction in up to 8 years follow-up). CONCLUSIONS: Response to aspirin does not seem to have a role in determining long-term outcome in patients with symptomatic PAD. The fact that testing of platelet function at only one time point has reduced significance may have implications for all clinical settings in which aspirin is used for the prevention of thrombo-embolic events.

Wall shear stress in the superficial femoral artery of healthy adults and its response to postural changes and exercise.

OBJECTIVES: Alterations of wall shear stress (WSS) are considered to precede atherosclerosis. Local variations of WSS might contribute to the typical distribution of atherosclerotic lesions along the superficial femoral artery (SFA). We investigated the course of WSS and its response to postural changes and exercise along the SFA of healthy adults. METHODS: In forty-six healthy subjects, we determined flow velocities and internal vessel diameters in five predefined segments of the SFA using duplex ultrasound; measurements were done at rest, following exercise (30 toe raises) and after postural changes (supine and sitting). Peak and mean WSS were calculated from peak systolic and mean velocities, vessel diameter and whole blood viscosity. RESULTS: At rest, peak and mean WSS did not vary along the femoro-popliteal axis (p > 0.05); peak and mean WSS were lower in the sitting than in the supine position (p < 0.0001). After exercise, peak and mean WSS increased in all segments (p < 0.0001), showing the lowest increase in the distal Hunter's canal. CONCLUSION: Healthy adults do not exhibit local variations of WSS in the SFA at rest, but segmental differences in WSS occur after exercise. Whether these findings are related to the typical distribution of atherosclerotic lesions later in life requires further investigation.

Follow-ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: levels and 6-year changes in risk factors.

OBJECTIVES: To examine cardiovascular risk factor levels in 2007 and their 6-year changes between 2001 and 2007 using the data collected in the follow-ups of the Cardiovascular Risk in Young Finns Study. DESIGN: Population-based follow-up study. SUBJECTS: A total of 2204 healthy Finnish adults aged 30-45 years (1210 women; 994 men). MAIN OUTCOME MEASURES: Levels in 2007 and changes between 2001 and 2007 of lipids, insulin, glucose, blood pressure, smoking, body mass index, alcohol consumption, waist and hip circumferences. RESULTS: The mean serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride concentrations in 30- to 45-year-old adults were 5.05, 3.09, 1.34 and 1.40 mmol L(-1), respectively. Significant changes (P < 0.05) between 2001 and 2007 in 30- to 39-year-old subjects included a decrease in total cholesterol (-6.6% in men, -5.8% in women), LDL-cholesterol (-10.2% and -11.6%) and an increase in diastolic blood pressure (3.5% and 3.9%). Waist circumference (1.8% and 5.5%) and systolic blood pressure increased in 36-39 year olds (2.3% and 2.3%). HDL-cholesterol increased in 30- to 33-year-old women (5.8%) Glucose levels increased in 30- to 39-year-old women (3.7%) and 36- to 39-year-old men (3.6%). Smoking prevalence decreased in 36- to 39-year-old men from 29.8% to 22.2%. CONCLUSIONS: The 6-year changes in total cholesterol, LDL-cholesterol and HDL-cholesterol in young Finns were favourable between 2001 and 2007. However, waist circumference, glucose and blood pressure levels increased. Therefore, continuous efforts are still needed in fighting against cardiovascular risk factors.

Lack of major gender-related differences in patients undergoing elective endovascular or surgical repair of abdominal aortic aneurysm.

AIM: The aim of this single center retrospective study was to determine gender-related differences in patients undergoing repair of aortic aneurysm. METHODS: A total of 296 consecutive patients with an abdominal aneurysm undergoing elective endovascular or surgical repair was included in the study. Among these, 24 (8.1%) were females and 272 (91.9%) were males. Demographic and clinical characteristics as well as laboratory values in terms of any potential gender-specific differences were compared. RESULTS: Females were significantly older at the time of repair than males. No gender-related differences were found analysing major clinical and laboratory parameters. CONCLUSIONS: The clinical and laboratory profile with which males and females present at the time of elective endovascular or surgical repair for aortic aneurysm is very similar. It does not reveal any potential gender-specific risk constellation. It eventually remains unclear why the prevalence of aortic aneurysm is higher in male than in females.

Movement of bromacil in a Hawaii soil under pineapple cultivation - a field study.

Recent discovery of low concentrations of bromacil in drinking water prompted the State of Hawaii to examine the leaching behavior of bromacil in pineapple fields. This study is a follow up to earlier work on bromacil concentrations in soil profiles in a pineapple field in central Oahu, Hawaii. Soil samples were collected for bromacil analysis at different times prior to and after application from a pineapple field that was previously surveyed by other research workers. The leaching pattern of bromacil was further investigated at two different application rates (2.25 and 1.8 kg ha(-1)). The concentration of bromacil in the topsoil about 100 days after bromacil application (1.8 kg ha(-1)) was substantially higher in 2002 compared to 1999. The distribution profiles were generally consistent with the one presented in the previous study. Residual bromacil was present in the entire sampled zone (3m deep) about 18 months after the previous bromacil application. Over a period of 9 months, there was substantial dissipation of bromacil residue present in the topsoil. The residual concentration of bromacil in the area that received the reduced application rate (1.8 kg ha(-1)) were lower than those receiving the current application rate (2.25 kg ha(-1)) and the depth of penetration of the bromacil front was shallower at the reduced application rate. Because of the common practice of placing plastic mulch around the base of the pineapple plants to retain volatile nematicides, the applied bromacil was found to be concentrated in the areas between the plastic mulch, transported by runoff from the plastic. The study results encourage the use of less than the label led rate of application of bromacil for pineapple fields.

Initial evaluation of 18F-fluorothymidine (FLT) PET/CT scanning for primary pancreatic cancer.

PURPOSE: The aim of this study was to evaluate the potential of (18)F-fluorothymidine (FLT) PET/CT for imaging pancreatic adenocarcinoma. METHODS: This was a pilot study of five patients (four males, one female) with newly diagnosed and previously untreated pancreatic adenocarcinoma. Patients underwent FLT PET/CT, (18)F-fluorodeoxyglucose (FDG) PET/CT, and contrast-enhanced CT scanning before treatment. The presence of cancer was confirmed by histopathological analysis at the time of scanning in all five patients. The degree of FLT and FDG uptake at the primary tumor site was assessed using visual interpretation and semi-quantitative SUV analyses. RESULTS: The primary tumor size ranged from 2.5 x 2.8 cm to 3.5 x 7.0 cm. The SUV of FLT uptake within the primary tumor ranged from 2.1 to 3.1. Using visual interpretation, the primary cancer could be detected from background activity in two of five patients (40%) on FLT PET/CT. By comparison, FDG uptake was higher in each patient with a SUV range of 3.4 to 10.8, and the primary cancer could be detected from background in all five patients (100%). CONCLUSIONS: In this pilot study of five patients with primary pancreatic adenocarcinoma, FLT PET/CT scanning showed poor lesion detectability and relatively low levels of radiotracer uptake in the primary tumor.

Factors affecting the likelihood of reporting road crashes resulting in medical treatment to the police.

OBJECTIVE: This paper aims to determine the percentage of road crashes resulting in injuries requiring hospital care that are reported to the police and to identify factors associated with reporting such crashes to the police. DESIGN: The data of one of two hospitals in the Road Casualty Information System were matched with the police's Traffic Accident Database System. Factors affecting the police-reporting rate were examined at two levels: the different reporting rates among subgroups examined and tested with chi2 tests; and multiple explanatory factors were scrutinised with a logistic regression model to arrive at the odds ratios to reflect the probability of police-reporting among subgroups. RESULTS: The police-reporting rate was estimated to be 57.5-59.9%. In particular, under-reporting among children (reporting rate = 33.6%) and cyclists (reporting rate = 33.0%) was notable. DISCUSSION: Accurate and reliable road crash data are essential for unveiling the full-scale and nature of the road safety problem. The police crash database needs to be supplemented by other data. In particular, any estimation about the social costs of road crashes must recognise the under-reporting problem. The large number of injuries not reflected in the police crash database represents a major public health issue that should be carefully examined.

Isolated ventricular non-compaction of the myocardium in adults.

Isolated ventricular non-compaction (IVNC) in adults is a genetic cardiac disease of emerging importance with a distinct clinical and pathophysiological presentation. The body of evidence for the underlying genetic basis of the disease has also grown. Prognosis remains poor for patients with impaired systolic left ventricular function, as treatment options are very limited. The diagnosis of IVNC, however, is often missed, most often as a consequence of ignorance of the condition. The relevant clinical issues and the emerging concepts of the aetiology of IVNC are summarised.