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Longitudinal analysis of serum oxylipin profile as a novel descriptor of the inflammatory response to surgery
Arnaud M. Wolfer1,
Alasdair J. Scott1,
Claudia Rueb2,
Mathieu Gaudin1,
Ara Darzi1,
Jeremy K. Nicholson1,
Elaine Holmes1,3 &
James M. Kinross1
Oxylipins are potent lipid mediators demonstrated to initiate and regulate inflammation yet little is known regarding their involvement in the response to surgical trauma. As key modulators of the inflammatory response, oxylipins have the potential to provide novel insights into the physiological response to surgery and the pathophysiology of post-operative complications. We aimed to investigate the effects of major surgery on longitudinal oxylipin profile.
Adults patients undergoing elective laparoscopic or open colorectal resections were included. Primary outcomes were serum oxylipin profile quantified by ultra high-performance liquid chromatography-mass spectrometry, serum white cell count and C-reactive protein concentration. Serum samples were taken at three time-points: pre-operative (day zero), early post-operative (day one) and late post-operative (day four/five).
Some 55 patients were included, of which 33 (60%) underwent surgery that was completed laparoscopically. Pre-operative oxylipin profiles were characterised by marked heterogeneity but surgery induced a common shift resulting in more homogeneity at the early post-operative time-point. By the late post-operative phase, oxylipin profiles were again highly variable. This evolution was driven by time-dependent changes in specific oxylipins. Notably, the levels of several oxylipins with anti-inflammatory properties (15-HETE and four regioisomers of DHET) were reduced at the early post-operative point before returning to baseline by the late post-operative period. In addition, levels of the pro-inflammatory 11-HETE rose in the early post-operative phase while levels of anti-thrombotic mediators (9-HODE and 13-HODE) fell; concentrations of all three oxylipins then remained fairly static from early to late post-operative phases. Compared to those undergoing laparoscopic surgery, patients undergoing open surgery had lower levels of some anti-inflammatory oxylipins (8,9-DHET and 17-HDoHE) in addition to reduced concentrations of anti-thrombotic mediators (9-HODE and 13-HODE) with increased concentration of their pro-thrombotic counterpart (TxB2).
Serum oxylipin profile is modified by surgical intervention and may even be sensitive to the degree of surgical trauma and therefore represents a novel descriptor of the surgical systemic inflammatory response.
Complications following colorectal surgery, such as surgical site infection (2–25% [1, 2]) and anastomotic leak (3–15% [3]), frequently induce the systemic inflammatory response syndrome (SIRS) or sepsis which are the major causes of post-operative morbidity and mortality [3–6]. To detect such complications, clinicians are generally reliant on the longitudinal assessment of physiological parameters (e.g. respiratory rate, heart rate, temperature) and biomarkers of inflammation, such as C-reactive protein (CRP) and white cell count (WCC). However, pertubations in these parameters are the final common pathway of many distinct pathologies and are therefore relatively late indicators and are extremely non-specific. A more detailed understanding of the inflammatory response and the ability to quantify it with higher resolution may enhance the early detection of acute post-operative complications.
Eicosanoids, and more generally oxylipins, are potent, locally-acting lipid mediators derived from the metabolism of polyunsaturated fatty acid (PUFA) precursors such as linoleic acid (C18:2, LA), dihomo-γ-linolenic acid (C20:3, DGLA), arachidonic acid (C20:4, AA), eicosapentaenoic acid (C20:5, EPA) and docosahexaenoic acid (C22:6, DHA). These PUFAs are principally converted to biologically active downstream mediators by three enzymatic pathways. Cyclooxygenase (COX) produces prostaglandins (PG) and thromboxanes (Tx), while lipoxygenase (LOX) produces leukotrienes (LT). Finally, cytochrome P450 (CYP450), together with LOX, is responsible for generating the less well-characterised "non-classical" eicosanoids including AA-derived hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs), LA-derived hydroxyoctadecadienoic acids (HODEs) and DHA-derived hydroxy-docosahexaenoic acids (HDoHEs). Oxylipins form a complex of interlinked cascades with a variety of precursors and metabolites that may or may not have biological activity. The biological effects of oxylipins are diverse, pleiotropic, antagonistic and, in some cases, still unclear. However, their ability to regulate the propagation and resolution of inflammation via effects on smooth muscle, cytokine release, the coagulation cascade and leukocyte chemotaxis is well-described [7–9]. Despite the acknowledged importance of oxylipins, there remains an incomplete knowledge of their systemic profiles during acute inflammation in humans due to a lack, until recently, of suitable quantitative bioanalytical platforms.
We have previously described a novel, highly sensitive assay for the detection in biofluids of a panel of oxylipins and PUFAs spanning the major PUFA precursors and the three principal biosynthetic enzyme pathways (CYP450, COX and LOX) [10]. In the present study, we applied this assay to longitudinally quantify the serum levels of key oxylipins in patients undergoing colorectal surgery. The aims of our investigation were, (1) to provide proof-of-principle that multiple oxylipin concentrations can be quantified simultaneously in human biofluids in the clinical environment and; (2) to better characterise the evolution of the oxylipin profile in response to surgical trauma. We hypothesise that the serum oxylipin profile may provide novel insights into the inflammatory response to surgery and perhaps ultimately show potential as an early biomarker of inflammatory dysregulation.
Patients and samples
This longitudinal observational investigation was conducted at St Mary's Hospital in London, UK, from January 2012 to April 2013. All patients over the age of 18 undergoing laparoscopic or open elective colorectal resections for both benign and malignant conditions were prospectively recruited to the study by a research nurse on the morning of surgery. Operative approach (e.g. open or laparoscopic) was at the discretion of the operating surgeon and patient and there were no absolute criteria for either. Patients undergoing emergency surgery and those unable to give informed consent were excluded. All patients received standard prophylactic antibiotic treatment on induction of general anaesthesia and were managed post-operatively according to a standardised enhanced recovery program [11].
Primary outcome was the biochemical and inflammatory response to surgery measured by the serum oxylipin profile, white cell count and C-reactive protein concentration. Secondary outcomes included the development of post-operative complications and length of stay. Post-operative complications included anastomotic leak (proven on imaging), severe sepsis (defined according to guidelines from the Surviving Sepsis Campaign [12]) and death. Blood was sampled into serum separator Vacutainers (Becton–Dickinson, Oxford, UK) pre-operatively and daily after surgery until 14 days post-operatively or discharge (whichever came sooner). Blood was allowed to clot in the Vacutainer before being centrifuged at 1200g for 10 min to obtain serum that was then frozen (−80 °C) until analysis.
Mass spectrometric quantification of oxylipins
Sample preparation and the quantification of lipid mediators by ultra high-performance liquid chromatography (UPLC)-mass spectrometry followed the previously published method of Wolfer et al. [10], resulting in the quantification of 21 oxylipins and PUFAs (Table 1). The procedure is described in detail in the Additional file 1 and summarised below. Sample preparation consisted of a solid phase extraction (Oasis MAX µElution, Waters, Milford, USA) of 100 µL serum spiked with deuterated internal standards (Cayman Chemical, MI, USA) to account for variation in extraction yields and instrumentation. UPLC enabled the separation of all oxylipins and PUFAs in 13 min with a HSS T3 UPLC (100*1 mm, 1.8 μm) column maintained at 40 °C on an Acquity UPLC and samples maintained at 4 °C. The mobile phases consisted of H2O + 0.1% formic acid (A) and acetonitrile + 0.1% formic acid (B), with a flow rate of 0.14 mL/min. Negative ionisation mode multiple reaction monitoring mass spectrometry enabled the selection of the most specific and sensitive ion for the quantification of each analyte (Additional file 1: Figures S1, S2) using a Xevo TQ-S triple quadrupole mass spectrometer (Waters, Milford, USA). For each batch of 96 samples, a calibration curve was prepared by serial dilution of a mixture of oxylipin (1 ng/μL to 0.01 pg/μL) and PUFA (10 ng/μL to 0.1 pg/μL) standards (Caymen Chemical) in MeOH/H2O 1:1 and sample analyte concentrations were calculated from the standard curve. Peak detection, integration and quantification were achieved using the Masslynx and TargetLynx software (Waters, Manchester, UK) and further manual verifications.
Table 1 Summary of quantified oxylipins and PUFAs including their metabolism and principal biological activity
Univariate analysis was performed in R v3.1.3 (Foundation for Statistical Computing, Vienna, Austria) [13]. Patients' demographic and clinical characteristics are reported as median (interquartile range [IQR]) and statistical comparisons were by Mann–Whitney U or Fisher's exact tests as appropriate. Changes in oxylipin concentration between time-points are reported as median fold change (IQR) and assessed by paired t-tests with application of the Benjamini-Hochberg false discovery rate. Oxylipin concentrations at each time-point were paired with WCC and CRP measurements taken on the same day. WCC and CRP concentrations and associated heat-maps were generated using in-house scripts and plotted using the ggplot2 package [14]. Significance testing of correlation coefficients was achieved by t tests.
Multivariate analysis was performed in R v3.1.3 and SIMCA-P v13 (Umetrics AB, Umeå Sweden). Prior to analysis, analyte concentrations were mean-centred and scaled to unit-variance. Unsupervised (principal component analysis [PCA]) and supervised (partial least squares discriminant analysis [PLS-DA]) methods were employed to visualise and interpret the oxylipin profile in the context of clinical variables including time-point and surgical approach. Goodness of fit of multivariate models was evaluated by the proportion of variance explained by the model (R2X) and the predicative ability was estimated by cross-validation (Q2Y) and permutation testing (1000 permutations, p value reported).
Some 55 patients were recruited during the 16 month study period—30 females and 25 males. Patient demographics and clinical data are presented in Table 2. During the early post-operative period (up to 30 days or discharge from hospital) a total of five patients (9%) suffered an anastomotic leak and four (7%) developed severe sepsis (three following an anastomotic leak and one with strangulated small bowel in an incisional hernia). One patient (~2%) died.
Table 2 Demographic, clinical and surgical characteristics of the recruited population
Table 2 provides a comparison of demographic variables between patients undergoing open (n = 22, including conversions) versus laparoscopic surgery. Patients in the laparoscopic cohort had a significantly lower BMI (25 [23,24,25,26,27] vs. 28.5 [25,26,27,28,29,30,31,32], p = 0.013) than patients undergoing open surgery and were more likely to be female (61 vs. 23%, p = 0.013). There were no differences in the procedures, underlying pathologies or development of post-operative complications between the two groups. However, patients undergoing laparoscopic surgery had a significantly shorter length of stay (7 [6,7,8,9,10] vs. 10 [8,9,10,11,12,13,14,15], p = 0.047).
To simplify our analysis of the evolving oxylipin profile over time we grouped samples into three defined time-points: pre-operative (day zero), early post-operative (day one) and late post-operative (day four or five, depending on sample availability). A total of 31/55 patients provided a pre-operative sample, 41/55 provided an early post-operative sample and 29/55 provided a late post-operative sample.
Surgery induces time-dependent shifts in serum oxylipin profiles
Pre-operatively (Fig. 1a), patients are widely dispersed across the PCA scores plot of their serum oxylipin profiles suggesting significant baseline heterogeneity. In contrast, in the early post-operative phase (day one, Fig. 1b), patients form a tight cluster, implying that surgery induces a common shift in oxylipin profile, which overwhelms the baseline heterogeneity. By the late post-operative time-point (day four, Fig. 1c), patients are again more widely dispersed in the scores plot, regaining significant variability in their oxylipin profiles. Notably, nearly all the outliers from the three time-points (defined by Hotelling's T2 ellipse) are from the pre-operative phase. These data suggest that although patients may have very different resting oxylipin profiles, they exhibit a similar deviation in response to surgical trauma. However, this homogenous response quickly gives way to renewed heterogeneity as patients follow different inflammatory trajectories during their recovery.
Principal component analysis scores plots of pre- and post-operative oxylipin profiles, highlighting: a significant pre-operative variability (pre-operative day, red); b the common deviation induced by surgery at the early post-operative time-point (day one, green) and; c renewed heterogeneity by the late post-operative phase (day four, blue)
We also constructed partial least squares discriminant analysis (PLS-DA) models to determine if oxylipin profiles alone could be used to differentiate between operative time-points. PLS-DA models demonstrated moderate ability to distinguish between pre-operative and early post-operative samples based on the variance explained by the model (R2X = 0.37) and the ability of the model to predict the timepoint (Q2Y = 0.24, permutation p < 0.001). PLS-DA models comparing early and late post-operative samples (R2X = 0.28, Q2Y = 0.22, permutation p < 0.001) and between pre-operative and late post-operative samples (R2X = 0.32, Q2Y = 0.39, permutation p < 0.001) were also statistically significant.
Surgery induces time-dependent concentration changes in specific oxylipins
To quantify how the concentrations of specific oxylipins changed over time in response to surgery we compared paired (i.e. from the same patient) oxylipin concentrations between pre-operative and early post-operative time-points, early and late post-operative time-points and pre-operative and late-post-operative time-points. CRP concentration and WCC were similarly compared between time-points to provide a known reference of inflammation. Results are described in Table 3 as median fold changes (IQR) for each metabolite between the specified time-points. As expected, compared to pre-operative samples, both WCC (1.44-fold, p < 0.0001) and CRP (30.00-fold, p = 0.007) were significantly elevated at the early post-operative point. The pro-inflammatory mediator 11-HETE was also elevated (1.47-fold, p = 0.005). At the same time, there was a significant decreases in the concentration of a number of oxylipins reported to have anti-inflammatory effects including 15-HETE (0.63-fold, p = 0.005), all four regioisomers of dihydroxyeicosatrienoic acid (DHET) and a trend to reduction in the concentration of 8-HETE (0.74-fold, p = 0.052). We also noted reductions in the levels of two lipid mediators with anti-thrombotic effects, 9-HODE (0.71-fold, p = 0.028) and 13-HODE (0.72-fold, p = 0.039).
Table 3 Changes in the concentrations of specific oxylipins, CRP and WCC between time-points
Some of these changes were reversed in the transition from the early to late post-operative time-point. WCC was significantly reduced (0.78-fold, p = 0.045) and the concentrations of the anti-inflammatory 8-HETE (1.54-fold, p = 0.011) and three of the regioisomers of DHET had all risen towards baseline levels. However, concentrations of 11-HETE showed a trend towards further elevation (1.20-fold, p = 0.068), while CRP, 9-HODE and 13-HODE remained fairly static. Levels of the relatively inactive stable degradation product of the pro-inflammatory leukotriene B4, 12-oxo-LTB4, which had demonstrated a trend towards reduction at the early post-operative phase, also remained static and were found to be nearly half their pre-operative values by the late post-operative time-point (0.51-fold, p = 0.039).
Correlation between oxylipins and other known mediators of inflammation over time
The relationship between oxylipins and known mediators of inflammation in response to a surgical stimulus is unknown. Therefore, we correlated each mediator with CRP concentration and WCC at each time-point and generated correlation heatmaps of the results (Fig. 2; Additional file 1: Table S1). The majority of statistically significant correlations between WCC, CRP and oxylipins were observed pre-operatively. However, none of these associations persisted consistently at both the early and late post-operative time points. 5-HETE was negatively correlated with WCC pre-operatively (r = −0.53, p = 0.0031) and at the early post-operative phase (r = −0.31, p = 0.05) but this association was lost by the late post-operative time-point (r = −0.1, p = 0.41). In fact, at the late post-operative point, there were no significant correlations between individual oxylipin levels and WCC or CRP concentrations. As expected, we did observe strong positive correlations at all time-points between specific oxylipins and their corresponding PUFA precursors (e.g. 5-HETE and arachidonic acid) and between oxylipins sharing the same biosynthetic cascade (e.g. 8-HETE and 15-HETE synthesised by arachidonate 15-lipoxygenase), which supports the validity of our assay (Additional file 1: Figure S3).
Pearson correlation heat maps between CRP, WCC and oxylipins at the pre-operative, early post-operative and late post-operative time-points. Correlation values are reported for correlations with a p value <0.05 (by t test). Red cells indicate positive correlation and blue cells negative correlation
Post-operative oxylipin profile differs between open and laparoscopic surgery
Open surgery may result in a greater traumatic burden to the patient than laparoscopic surgery [15–21], which might be reflected in differences in their post-operative oxylipin profiles. We therefore generated PLS-DA models to investigate if post-operative WCC, CRP concentration and oxylipin profile could discriminate between open and laparoscopic surgery. A model at the early post-operative time-point (R2X = 0.09, Q2Y = −0.15, permutation p = 0.36) was unable to discriminate reliably but at the late post-operative point, the inflammatory panel demonstrated a modest capacity to predict the operative approach (R2Y = 0.28, Q2Y = 0.11, permutation p < 0.001).
We then compared mean oxylipin concentrations between patients undergoing open versus laparoscopic surgery at each time-point (represented by boxplots [22] in Fig. 3). As expected, open and laparoscopic surgery groups displayed no baseline differences in oxylipin concentration at the pre-operative time-point. However, by the early post-operative time-point significant differences between the two groups were noted. Specifically, patients undergoing open surgery had lower levels of 8,9-DHET (on average 29% lower, p = 0.047), a stable degradation product of the anti-inflammatory epoxyeicosatrienoic acid and lower concentrations of the anti-thrombotic 9-HODE (on average 31% lower, p = 0.0052) and 13-HODE (on average 14% lower, p = 0.048) compared to patients undergoing laparoscopic surgery. Furthermore, TxB2 (an inactive metabolite of platelet-activating TxA2) concentration was elevated in the open group (on average 194% higher, p = 0.043), while there was a trend towards elevated concentrations of 6-keto-PGF1α (inactive metabolite of PGI2, the physiological antagonist of TxA2) in the laparoscopic group (on average 79% higher, p = 0.068). Both of these differences persisted into the late post-operative phase, when we also found higher levels of 17-HDoHE (on average 29% higher, p = 0.049), a potent anti-inflammatory mediator, and its precursor DHA (on average 51% higher, p = 0.05) in patients undergoing laparoscopic surgery. Lastly, concentrations of the PUFA precursor EPA were elevated in the laparoscopic group at both post-operative time-points. There were no significant differences in WCC or CRP concentration between the two surgical approaches at either post-operative time-point.
Boxplots of relative concentrations for the oxylipins that differed significantly between laparoscopic (green) and open surgery (blue) at the early post-operative (left) and late post-operative time-points (right). All boxplots of concentration (y-axis) start at 0 and the scale is preserved for each oxylipin across time and surgery. The bottom and top of each box represent the 1st and 3rd quartiles respectively, while the centre band represents the median value [22]. Whiskers extend to one standard deviation above and below the mean of the data, while measurements past the whiskers are plotted as possible outliers by a dot
Oxylipins, such as prostaglandins and leukotrienes, have been individually studied for over fifty years but technological limitations restricting the number of oxylipins that could be simultaneously assayed have necessarily focussed work on allocating distinct regulatory functions to individual mediators [23, 24]. Recent developments in analytical platforms allowed us to develop an assay for the simultaneous analysis of numerous lipid mediators in biofluids [10]. In the present investigation we applied this oxylipin assay to adult patients undergoing elective colorectal surgery to demonstrate that oxylipin profiling is feasible in a clinical context and that it has the potential to provide novel insights into the systemic inflammatory response.
PCA of oxylipin profiles demonstrated that surgery induces profound time-dependent shifts. We observed significant variability amongst pre-operative oxylipin profiles that may reflect the heterogeneity in the demographics (e.g. age, gender, physical condition), underlying aetiologies, attendant comorbidities and pre-operative preparations of the patient population. However, it should be noted that previous studies have shown that even when individuals were well-matched with regard to gender, health and physical condition, their basal oxylipin levels still differed significantly [25]. Despite this underlying heterogeneity, surgery induced a more uniform oxylipin profile at the early post-operative phase, perhaps reflecting a coherent response to surgical trauma. By the late post-operative phase, significant variability in oxylipin profile was again noted, perhaps reflecting unique recovery trajectories between patients. Visual differences between the PCA scores plots were confirmed by supervised multivariate analysis which was able to discriminate between each time-point on the basis of the oxylipin profile.
Univariate analysis of individual oxylipin concentrations revealed that, compared to pre-operative levels, there was a generalised dampening of several anti-inflammatory (15-HETE, 8-HETE and degradation products of EET) and anti-thrombotic (9-HODE and 13-HODE) mediators, combined with an increase in the pro-inflammatory 11-HETE. In the late post-operative phase, the levels of anti-inflammatory mediators were typically elevated compared to the early post-operative time-point suggesting a return towards baseline and indeed, no significant differences were observed for these mediators between the pre-operative and late post-operative samples. In contrast, the pro-inflammatory 11-HETE and anti-thrombotic 9-HODE and 13-HODE did not appear to return to baseline, although the differences between pre-operative and late post-operative measurements were non-significant. Interestingly, levels of 12-oxo-LTB4 (the stable degradation product of pro-inflammatory leukotriene B4) showed a trend towards reduction at the early post-operative point and were significantly reduced by the late post-operative phase. We attempted to correlate oxylipin concentrations with with CRP concentration and WCC as known references of inflammation. However, no consistent correlations we found, perhaps reflecting temporal differences in the dynamics of oxylipin, CRP and WCC levels [26, 27]. When interpreting our results it is important to bear in mind that, due to the lipid mediator's bioactivity as inflammatory signalling compounds, sample collection and handling could result in in vivo and ex vivo alterations [28]. For example, the stimulation of platelets and leukocytes following venipuncture and serum formation could potentially cause activation of the oxylipin biosynthetic cascade [29]. Equally, anticoagulants used for the collection of plasma (such as heparin) can stimulate oxylipin production via activation of phospholipase A2 [30, 31]. However, the practicalities of collecting samples within a clinical environment limit the extent to which such potential effects can be prevented.
Although it is interesting to postulate on how changes in the oxylipin profile fit with the current understanding of the inflammatory response to surgery, we urge caution to avoid overstating and oversimplifying the results of our single study. That said, the early reduction in the concentration of mediators with anti-inflammatory and anti-thrombotic effects could be viewed as "releasing the brake" on inflammation, consistent with the pro-inflammatory, pro-thrombotic phenotype that is thought to dominate the early post- operative phase [32, 33]. Early elevation of pro-inflammatory 11-HETE would also support this hypothesis. The subsequent return of the anti-inflammatory mediators towards basal levels may reflect a reinstatement of normal inflammatory homeostasis. Evidence of early and persistent reduction in the pro-inflammatory leukotriene B4 may seem contrary to this hypothesis but other investigations have demonstrated that leukotriene B4 release by neutrophils peaks extremely rapidly following surgery (e.g. within 6 h) and that levels remain low thereafter [34, 35]. The early post-operative sample in the present study was taken at 24 h, and may well have missed an initial peak in pro-inflammatory oxylipin concentration, leaving only the later nadir. Strassburg et al. recently investigated the effects of on-pump cardiac surgery on serum oxylipin levels in five patients and demonstrated increases in other oxylipins with pro-inflammatory effects at 24 h post-operatively, including 12-HETE and 5-HETE which were quantified in our assay [36]. However, the large physiological insult of on-pump cardiac surgery, small sample size and discrepancies in their sampling protocol (venous blood pre-operatively and arterial blood post-operatively) makes direct comparison between our investigations difficult.
The immunophysiological impact of laparoscopic versus open colorectal surgery is not well understood with conflicting evidence [15–21]. Our investigation was not powered to detect differences in oxylipin profile by outcome (e.g. the development of complications) or by surgical approach as patients were not randomised. With these caveats, we did find that length of stay was shorter in the laparoscopic group and demonstrated interesting differences in the post-operative oxylipin profiles between the two approaches. Patients undergoing open surgery had lower levels of some anti-inflammatory oxylipins (8,9-DHET and 17-HDoHE) in addition to reduced concentrations of anti-thrombotic mediators (9-HODE and 13-HODE) with increased concentration of their pro-thrombotic counterpart (TxB2). Higher levels of anti-inflammatory 17-HDoHE were found amongst the laparoscopic cohort. Whilst almost certainly an oversimplification, these results could be suggestive of a more pro-inflammatory, pro-thrombotic phenotype amongst patients undergoing open surgery.
This is the first investigation to quantify systemic oxylipin profile longitudinally in a cohort of patients undergoing major surgery. We have demonstrated that surgery induces a common shift in lipid mediators, marked at 24 h post-operatively by a combination of elevation in pro-inflammatory oxylipin concentration with suppression of specific oxylipins thought to have anti-inflammatory and/or anti-thrombotic effects. Furthermore, differences between patients undergoing open versus laparoscopic surgery suggests that the oxylipin profile may be sensitive to the degree of surgical trauma. Based on this evidence, the stage is set to more completely define the "normal" oxylipin dynamics in response to surgery using a more comprehensive sampling strategy and a larger patient cohort. Deviations from this "normal" profile may then offer a useful prognostic tool for the early identification of patients at higher risk of post-operative complications.
arachidonic acid (C20:4)
COX:
CYP450:
DHA:
docosahexaenoic acid (C22:6)
DHET:
dihydroxyeicosatrienoic acid
EET:
epoxyeicosatrienoic acid
EPA:
eicosapentaenoic acid (C20:5)
HDoHE:
hydroxydocosahexaenoic acid
HETE:
hydroxyeicosatetraenoic acid
HODE:
hydroxyoctadecadienoic acid
IQR:
inter-quartile range
intensive treatment unit
linoleic acid (C18:2)
LOX:
LT:
leukotriene
PCA:
PG:
PLS-DA:
partial least squares-discriminant analysis
PUFA:
polyunsaturated fatty acid
SIRS:
systemic inflammatory response syndrome
Tx:
UPLC:
ultra-high performance liquid chromatography
WCC:
white blood cells count
Tang R, Chen HH, Wang YL, Changchien CR, Chen J-S, Hsu K-C, et al. Risk factors for surgical site infection after elective resection of the colon and rectum: a single-center prospective study of 2809 consecutive patients. Ann Surg. 2001;234:181–9.
Blumetti J, Luu M, Sarosi G, Hartless K, McFarlin J, Parker B, et al. Surgical site infections after colorectal surgery: do risk factors vary depending on the type of infection considered? Surgery. 2007;142:704–11.
Kirchhoff P, Clavien P-A, Hahnloser D. Complications in colorectal surgery: risk factors and preventive strategies. Patient Saf Surg. 2010;4:1–13.
Platell C, Barwood N, Dorfmann G, Makin G. The incidence of anastomotic leaks in patients undergoing colorectal surgery. Color Dis. 2007;9:71–9.
Köckerling F, Rose J, Schneider C, Scheidbach H, Scheuerlein H, Reymond MA, et al. Laparoscopic colorectal anastomosis: risk of postoperative leakage. Results of a multicenter study. Laparoscopic Colorectal Surgery Study Group (LCSSG). Surg Endosc. 1999;13:639–44.
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–54.
Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LAJ, et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21:325–32.
Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am J Pathol. 2010;177:1576–91.
Bannenberg G, Serhan CN. Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim Biophys Acta. 2010;1801:1260–73.
Wolfer AM, Gaudin M, Taylor-Robinson SD, Holmes E, Nicholson JK. Development and validation of a high-throughput ultrahigh-performance liquid chromatography-mass spectrometry approach for screening of oxylipins and their precursors. Anal Chem. 2015;87:11721–31.
Basse L, Hjort Jakobsen D, Billesbølle P, Werner M, Kehlet H. A clinical pathway to accelerate recovery after colonic resection. Ann Surg. 2000;232:51–7.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637.
R Foundation for Statistical Computing. R: a language and environment for statistical computing. Vienna, Austria 2015. https://www.r-project.org.
Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.
Cummings LC, Delaney CP, Cooper GS. Laparoscopic versus open colectomy for colon cancer in an older population: a cohort study. World J Surg Oncol. 2012;10:31.
Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AM, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet. 2005;365:1718–26.
Kennedy RH, Francis EA, Wharton R, Blazeby JM, Quirke P, West NP, et al. Multicenter randomized controlled trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme: EnROL. J Clin Oncol. 2014;32:1804–11.
Braga M, Vignali A, Gianotti L, Zuliani W, Radaelli G, Gruarin P, et al. Laparoscopic versus open colorectal surgery: a randomized trial on short-term outcome. Ann Surg. 2002;236:759–66.
Wichmann MW, Hüttl TP, Winter H, Spelsberg F, Angele MK, Heiss MM, et al. Immunological effects of laparoscopic vs open colorectal surgery: a prospective clinical study. Arch Surg. 2005;140:692–7.
Tsamis D, Theodoropoulos G, Michalopoulos VN, Nikiteas N, Tsigris C, Leandros E. Inflammatory response after laparoscopic versus open colonic resection: review of the literature. Int J Med Med Sci. 2010;2:106–10.
Kashihara H, Shimada M, Kurita N, Iwata T, Nishioka M, Morimoto S, et al. Comparisons of inflammatory cytokines expressions in drain after laparoscopic versus open surgery. Hepatogastroenterology. 2014;61:379–81.
Krzywinski M, Altman N. Visualizing samples with box plots. Nat Methods. 2014;11:119–20.
Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983;220:568–75.
Bergstrom S, Samuelsson B. Prostaglandins. Annu Rev Biochem. 1965;34:101–8.
Helmersson J, Basu S. Intra-day variation of in vivo prostaglandin F2alpha formation in healthy subjects. Prostaglandins Other Lipid Mediat. 2006;80:93–9.
Buczynski MW, Dumlao DS, Dennis EA. An integrated omics analysis of eicosanoid biology. J Lipid Res. 2009;50:1015–38.
Black S, Kushner I, Samols D. C-Reactive Protein. J Biol Chem. 2004;279:48487–90.
Tsikas D, Zoerner A. Analysis of eicosanoids by LC-MS/MS and GC-MS/MS: a historical retrospect and a discussion. J Chrom B. 2014;964C:79–88.
Schweer H, Kammer J, Kühl PG, Seyberth HW. Determination of peripheral plasma prostanoid concentration: an unreliable index of 'in vivo' prostanoid activity. Eur J Clin Pharmacol. 1986;31:303–5.
Nakamura H, Kim DK, Philbin DM, Peterson MB, Debros F, Koski G, et al. Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery. J Clin Invest. 1995;95:1062–70.
Goodfriend TL, et al. Heparin, lipoproteins, and oxygenated fatty acids in blood: a cautionary note. Prostaglandins Leukot Essent Fatty Acids. 2007;77:363–6.
Marik PE, Flemmer M. The immune response to surgery and trauma. J Trauma Acute Care Surg. 2012;73:801–8.
Kohl BA, Deutschman CS. The inflammatory response to surgery and trauma. Curr Opin Crit Care. 2006;12:325–32.
Sane S, Baba M, Kusano C, Shirao K, Kamada T, Aikou T. Effect of surgery on neutrophil leukotriene B4 generation and arachidonic acid content. Eur Surg. 1998;30:334–40.
Gu YJ, van Oeveren W, Boonstra PW, de Haan J, Wildevuur CR. Leukocyte activation with increased expression of CR3 receptors during cardiopulmonary bypass. Ann Thorac Surg. 1992;53:839–43.
Strassburg K, Huijbrechts AML, Kortekaas K, Lindeman JH, Pedersen TL, Dane A, et al. Quantitative profiling of oxylipins through comprehensive LC–MS/MS analysis: application in cardiac surgery. Anal Bioanal Chem. 2012;404:1413–26.
CR collected the clinical samples. MG developed the analytical method and processed the clinical samples. AMW processed the samples, performed data analysis, and wrote the manuscript. AJS and JMK performed data analysis and wrote the manuscript. JMK and AD supervised sample collection. EH, JKN and JMK supervised the research project. All authors read and approved the final manuscript.
The authors would like to thank the Imperial College Clinical Phenotyping Centre (CPC) which is is a core facility of the NIHR Imperial Biomedical Research Centre's (BRC) Institute of Translational Medicine and Therapeutics (ITMAT). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
The authors declare that they no competing interests.
The datasets generated and analysed during the current study are available from the corresponding author on request.
Ethical approval for this investigation was obtained from the London Regional Ethics Committee (REC 11/LO/0686) and the Joint Research Compliance Office at Imperial College Healthcare NHS Trust.
The authors acknowledge funding by the NIHR Imperial Biomedical Research Centre's (BRC) Institute of Translational Medicine and Therapeutics (ITMAT) funding scheme. AW acknowledges financial support by Technologie Servier through the Imperial College Stratified Medicine Graduate Training Program in Systems Medicine and Spectroscopic Profiling (STRATiGRAD). MG acknowledges funding from Technologie Servier.
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
Arnaud M. Wolfer, Alasdair J. Scott, Mathieu Gaudin, Ara Darzi, Jeremy K. Nicholson, Elaine Holmes & James M. Kinross
Imperial College Healthcare NHS Trust, London, UK
Claudia Rueb
Division of Computational and Systems Medicine, Faculty of Medicine, Imperial College London, 6th Floor, Alexander Fleming Building, South Kensington, London, SW7 2AZ, UK
Elaine Holmes
Arnaud M. Wolfer
Alasdair J. Scott
Mathieu Gaudin
Ara Darzi
Jeremy K. Nicholson
James M. Kinross
Correspondence to Elaine Holmes.
Additional file 1.
Supplementary material containing detailed methodology for mass spectrometric quantification of oxylipins, representative chromatograms and supplementary data.
Wolfer, A.M., Scott, A.J., Rueb, C. et al. Longitudinal analysis of serum oxylipin profile as a novel descriptor of the inflammatory response to surgery. J Transl Med 15, 83 (2017). https://doi.org/10.1186/s12967-017-1171-2
Metabonomics
Oxylipin
Clinical translation


text:
Officials and residents gathered at lighthouse Wednesday morning for designation of light as endangered structure.
Mark Lovewell
National Trust for Historic Preservation Declares Gay Head Light Endangered
Thursday, June 20, 2013 - 7:04pm
The National Trust for Historic Preservation announced in a ceremony at the Gay Head Cliffs Wednesday morning that it had named the Gay Head Light to its 2013 list of America's 11 Most Endangered Historic Places.
Members of the Gay Head Lighthouse committee, Martha's Vineyard Museum, selectmen from across the Island, U.S. Coast Guard and town residents gathered under the lighthouse to mark the announcement.
Beverly Wright urged entire Island to get involved with efforts to save lighthouse. — Mark Lovewell
The brick lighthouse dates to 1856 (it replaced a wooden tower built in 1799) and today sits perilously near the edge of a rapidly eroding cliff at the Island's westernmost edge. It is slated to be moved sometime in the next two years.
Alicia Leuba, field director for the National Trust for Historic Preservation, called the lighthouse an "iconic symbol" of the Vineyard and said she hoped the designation would be a "powerful tool" for rallying national support.
"The Gay Head Light embodies Martha's Vineyard's rich cultural heritage," she said. "The lighthouse's storied past is significant as a beacon to the Wampanoag tribal heritage, and its reflection of the country's nautical heritage makes it a national treasure that must be saved before it tumbles to the sea below."
Lenny Butler, who heads a town subcommittee charged with restoring and moving the light, served as master of ceremonies and welcomed the crowd to the historic site.
"We are honored to be designated to this year's list," he said.
The nomination was made by the Wampanoag Tribe of Gay Head (Aquinnah).
Alicia Leuba, field director for the National Trust for Historic Preservation: lighthouse is an "iconic symbol." — Mark Lovewell
Beverly Wright, a town selectman who is chairman of the town lighthouse committee, recalled growing up in Aquinnah and spending nights in neighboring fields playing a game of jump the beam. She said efforts to save the lighthouse stretched beyond Aquinnah, and she urged the entire Island to get involved.
"The Gay Head Light is ours but it is also yours," she said. "We're asking you to help save what belongs to all of us. Let the Gay Head Light keep on shining."
The announcement is the latest in a series of public spotlights on the historic tower, which is owned by the Coast Guard and managed by the Martha's Vineyard Museum. The U.S. government is expected to declare the lighthouse surplus property sometime this year, paving the way for a transfer of ownership to the town. The next step will be relocation of the light. Geological studies of the cliffs are already underway.
President Obama and his family visited the lighthouse in August 2009 when they were vacationing on the Island.
The National Trust for Historic Preservation annually names a list of 11 endangered historic places considered "at risk of destruction or irreparable harm." In addition to the Gay Head Light, the list this year includes the Abyssinian Meeting House in Portland, Me., the Houston Astrodome in Houston, Tex., and the Kake Cannery in Kake, Ala.
The designation does not come with funding but could pave the way for future funds to help restore and move the lighthouse.
The ceremony Wednesday also kicked off a fundraising campaign and new website for the lighthouse. It is now estimated that about $3 million will be needed to restore and move the structure. The lighthouse committee is investigating funding from private and public funds.
"We hope it will raise national awareness for other groups, foundations and individuals who read about it and think it's important," he said.
For more information or to make a donation, visit gayheadlight.org.
Gay Head Cliffs
Gay Head Light
Frank Adshead, La Verne, CA
My wife and I attempted to donate on-line to help preserve the Gay Head Lighthouse. We dislike providing our phone number to any person or organization on-line. Since you require phones numbers as a condition of donating, we regretfully discontinued our donation effort. If you make phjone numbers optional, we'll donate. F. Adshead
Adam Wilson, Aquinnah
Mr. Adshead, I am the Town Administrator for Aquinnah. We are currently working on doing just that - removing the telephone requirement. Please check back with us when the web site has made the necessary adjustment.
Paula Eisenberg, Gay Head Lighthouse Advisory Committee, Aquinnah
Mr. Adshead, thank you for wanting to help! Check are gratefully accepted. You can get the postal address at http://gayheadlight.org/contributions/.
William Waterway, Edgartown
This is a wonderful community effort. As many people know, I have been involved with saving and protecting the Gay Head Light for decades. Many thanks to the Town of Aquinnah and to the volunteers who serve on the Gay Head Lighthouse Committee.
August 26, 2013 - 4:43pm
Vineyard Voices
The Martha's Vineyard Museum is launching Vineyard Voices Three with a reception on Tuesday, July...
Museum Has Its Grand Opening, Summer-Style
Fireworks lit up the sky over Vineyard Haven Harbor Saturday night as a finale to the Evening of...
Aquinnah Looks to Outsource Assessor Position
Aquinnah moved one step closer to outsourcing its paid assistant assessor position with selectmen...
Time Machine >
Historical Society Makes Headway in Plan to Restore Oscar Pease's Catboat, Vanity
The Martha's Vineyard Historical Society doesn't have a whaling ship for its museum, nor a schooner.
Island History Comes Alive in Vineyard Voices
Vineyard Voices: Words, Faces and Voices of Island People. Excerpts from Interviews by Linsey Lee.
Society Wages Campaign for Lighthouses
Lighthouses define the character of Martha's Vineyard.

redpajama_set_name: RedPajamaCommonCrawl


Belief in Jesus brings us into relationship with God. In the previous chapter, the end of the story of Nicodemus we get the John 3:16 passage of God's great love for us. So much so, that righteousness is given to us as a gift, that if we believe we in Jesus, we may receive and enter into an eternal relationship with God. Relationship with God is the goal of Jesus' ministry. How do we overcome exclusiveness and build a community through inclusiveness?
In order to do this we have to wrestle with what we do with sin This weekend I went to the ETCL workshop at Iao UCC, on the Bible and Homosexuality. I don't like focusing on one sin in particular and hammering at it as the Church has done. I believe the UCC has had an approach more like Jesus has with the woman at the well, where there is no talk of condemnation but compassionate actions of a hope and grace, of worshiping together in Spirit and in truth.
Some of us hide our sin better than others. We act as if we have none so we are not truthful when we are critical of others. But if we were honest to the deep dark secrets of sin we harbor we would admit that all of us are in the same boat with God. And we all want to meet Jesus at the well to be accepted, to be known, to be treated with respect and loved.
The second part of the passage is about what happens when the disciples return and the woman's witness of Jesus in the village. Many Samaritans believed because of what the woman said. They asked Jesus to stay a few days, and he did. Then having heard Jesus for themselves they knew that Jesus was the Savior of the world.
The disciples came back from the village with provisions and wanted Jesus to eat. He was not hungry after his ministry to the woman. Doing the work of God feeds him. When I used to go fishing, and the fish were not biting, you were hungry, tired, hot, thirsty, and had to go use the bathroom. But when the fish are bitting you felt none of that.
People are ready to hear the message of salvation that Jesus brings. Jesus was encouraging his disciples to quicken the pace of talking to people about God because they are ready to hear the Good new he is brings to have their lives turned toward God.
Jesus traveled, intentionally into the area of Samaria to share the good news there. The message of Jesus crosses over all kinds of boundaries but mostly over the boundary of sin. We should not keep our stories about Jesus contained within our boundaries but be willing to share it as the Spirit leads.
This Friday Maile and I went to address the Committee on Ways and Means and the Finance Committee of the State. We have an application for a grant for from the state to help us with our mission ground project. They gave us a 3 minute opportunity to talk about our grant proposal. I did, in sermon form. I identified those who are looking for affordable housing as our neighbor, and those who need a place to gather and learn in our community center as our neighbor. Then I shared the story of the Good Samaritan in this way. "Who is my neighbor?" Is the question the Lawyer asks Jesus to define the boundaries of benevolence. Jesus' story of the Good Samaritan shatters the boundaries of prejudice to include the ignored, the marginalized and the wounded. They got a little theology with our request to extend our mission.
This weekend at the event at Iao I met a seeker who has been rejected by several other churches. He was unidentified as sin or otherwise, just as a fellow human being. But my hope was that if he came here he would find a welcome as we have felt. The story of the Jesus and the woman at the well is the illustration of John 3:17 for he did not come into the world to condemn the world but that the world might be saved through him. Because God so loves the world and has called us to do the same.


It's super easy to get castled-out in Europe, especially Denmark. There are too many damn castles everywhere! But Kronborg Castle caught my attention because of its location. With its strategic location on the northeastern tip of Zealand in Elsinore (just an hour's drive north of Copenhagen), sitting at the narrowest sound between Denmark and Sweden, it had to have a fascinating history. And it definitely did. For only kr 90 ($13) each, we were able to explore much of Kronborg at our own pace. Due to the number of rooms and galleries that were available to the public, Kronborg quickly became our favorite castle we have visited thus far.
One would think that a castle so beautiful would have been constructed for a royal family, but not at first. Instead of serving as a residential palace for royalty, Kronborg originally served as a tariff-collecting fortress, charging taxes for all ships passing through the 4-km wide sound for hundreds of years. It wasn't until later when Kronborg was converted into a residential palace once it was rebuilt into a magnificent Renaissance castle, and much of the royal family's original furniture are on current display. Shakespeare gave this castle fame when he made it the setting for Hamlet. From Kronborg's beautiful exterior, to the king's tapestries and the underground passageways, visitors can easily spend hours wandering and exploring the treasures on display.
Since we began the self-guided tour right when it opened, there were no lines and we enjoyed the exhibits all to ourselves. Hours later when we left the castle, crowds had formed and it was impossible to take a photo without other people in them. My advice is to arrive before the castle opens to walk the surrounding grounds, and then stroll through the exhibits upon opening. Kronborg is definitely worth the excursion outside of Copenhagen, especially on a sunny day.


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Further information on cookies should be available in the help pages of your browser, and most browsers will recognise when a cookie is offered and allow users to control how and when they are accepted. However, you should be aware that if you choose to decline cookies, you may not be able to fully experience all of the features of the Alistage website, and other websites that you choose to visit.
How does Alistage use cookies?
Alistage uses cookies that are strictly necessary to enable you to move around the site or to provide certain basic features. We use cookies to provide better functionality of the website by storing your preferences, for example. We also use cookies to help us to improve the performance of our website to provide you with a better user experience.
The information we collect using cookies is anonymous. We will never (and will not allow any third party to) use the statistical analytics tool to track or to collect any personally identifiable information of visitors to our site or associate your IP address with any other data held about you. We will not associate any data gathered from this site with any personally identifiable information from any source, unless you explicitly submit that information via a fill-in form on our website.
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Mariaweiler is een plaats in de Duitse gemeente Düren, deelstaat Noordrijn-Westfalen, en telt 2.744 inwoners (31-12-2020). Het dorp, dat vanaf de 3e eeuw tot in de middeleeuwen op een belangrijk wegenkruispunt lag, bevindt zich ten noordwesten van de stad Düren.

In het dorp staat een monumentaal, deels nog 19e-eeuws fabriekspand. Het is beschermd als industrieel erfgoed. In het pand is de Heimbach Filztuchfabrik gevestigd, die aan o.a. een soortgelijk bedrijf te Moresnet (België) is gelieerd. Er worden materialen van vilt en ander textiel geproduceerd, die weer bij de bouw van grote machines in andere takken van industrie, zoals drukpersen,  worden verwerkt.

Het grootste schoolgebouw van het dorp is naar het joodse meisje en Holocaust- slachtoffer Anne Frank genoemd. Als gedenkteken voor haar en ter vermanende waardering voor de normen en waarden, die door de nazi's systematisch met voeten zijn getreden is bij deze school een groot rechtopstaand steenblok geplaatst. Dit is een stèle van de hand van de bekende kunstenaar Ulrich Rückriem.

Düren
Plaats in Noordrijn-Westfalen

redpajama_set_name: RedPajamaWikipedia


text:
Hedwig van Driel PhD
Dutch patent attorney, European patent attorney, Belgian patent attorney
Hedwig van Driel
Physics, Software
Bachelor of Science at University College Utrecht
Master of Science in Theoretical Physics at Utrecht University PhD research
Hedwig started working at Arnold & Siedsma in 2014 as a trainee, and became a fully qualified Dutch, Belgian and European Patent Attorney in 2017. She has a background in theoretical physics, specifically cold atom physics. Her PhD research took place at Utrecht University and resulted in a thesis entitled ʻSpin Transport in Cold Bose Gases'.
At Arnold & Siedsma, Hedwig combines her affinity with language and her broad interest in science and technology. She is an expert in the fields of electronics, information technology and medical imaging, and in particular specializes in the prosecution of patents with claims comprising both technical and non-technical features, which are often found for instance in the software field. However, she also takes advantage of the diversity in types of work, clients and technical fields made possible by working in private practice.
She is furthermore actively involved in the company, amongst other things as a key member of an internal IT project and as a writer and editor of articles aimed at non-experts for the Arnold & Siedsma website.
Other people about Hedwig:
Geeky, critical, enthusiastic, open
2014 - present: Dutch patent attorney at Arnold & Siedsma
2006: Bachelor of Science at University College Utrecht
2008: Master of Science in Theoretical Physics at Utrecht University
2012: PhD research
Dutch, English, French, German
Contact us via Hedwig


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text:
rethink monthly
Tag Archives: Fleet Foxes
by bobegods | March 12, 2009 · 7:00 am
Review: Fiction Family
In a scene dominated by the gentle, hypersensitive sounds of Sufjan Stevens, The Welcome Wagon and Fleet Foxes, Jon Foreman and Sean Watkins finally inject some manliness back into the acoustic guitar.
Fiction Family, the culmination of two of our generation's most prolific and respected songwriters, debuts as a masterful collection of tales about murder, adventure, lost love, and war that highlight each contributor's strengths and personalities while managing to defy perceived expectations.
There's a beautiful carelessness to this project—a work birthed out of rest, friendship, and unabashed innovation. With no immediate deadlines, rules, or formats to follow, Foreman and Watkins embark on a musical journey of the purist, most unadulterated kind. The album keeps one foot in the folk door (a familiar home for both artists) while audaciously messing with everything from techno beats to '60s pop choirs to fisher price instruments. While the acoustic guitar remains fixed in the foreground, a symphonic cast of unlikely characters join the conversation. Chamber stings, tympanis, accordions and electric fuzz tones somehow manage to play nicely together. A few of the most arresting tracks replace traditional bass lines with resonate piano timbres, dark pounding drones that duel eloquently against intricate finger-picking patterns.
There's an idea that the farther one departs from the traditional pop format, the less tangible their work becomes to the average listener. Not so with Fiction Family. Wildly inventive and spontaneous (track two entitled "Out of Order" sounds exactly how it reads) the work stands in victorious defiance against a crumbling conventional music industry. Hooks and phrases linger long after their first introduction, and are sure to induce an involuntary foot-tapping episode or two.
It's the stories, however, that give the project a sense of timelessness. In the spirit of his Season EPs, Foreman channels cultural staples like Bob Dylan, Johnny Cash, even various Motown voices, conveying raw acoustic narratives like "Betrayal" and "War in My Blood" that read straight out of a great American novel. Watkins attaches his expertise for the hauntingly sorrowful love song that, in his case, always seems to relay more familiar truth than angsty longing. "Elements Combined" sketches the complexities of a woman, an intoxicating mixture of "earth, air, fire, and wine."
But it's not all love and war for the Family. Both Watkins and Foreman wrestle with the spiritual complexities of human nature. On "Closer Than You Think" the two critique the widely held notion of heaven as a distant and out of reach destination and suggest it may be "right under your feet." In traditional Foreman lyrical style, "Prove Me Wrong" is laden with tender screams for affirmation and acceptance as it contemplates every man's darkest struggles and fears through a solitary voice.
Those who have eased into a level of comfortable enjoyment of Jon Foreman's solo projects and Watkins' bluegrass repertoire may be caught off guard by the duo's progressive departure from the predictable. Those looking for Switchfoot meets Nickel Creek will be disappointed. This is truly a profound exploration deep into the creative wells of two tremendously inventive and forward-thinking songwriters. Fiction Family is genius. It's progressive without being high-brow, laid-back but fearless.
CJ is an artist, writer, and cultural commentator with a passion for raising a new generation of innovative artists and forward thinkers.
To download a free mp3 of Fiction Family's "When She's Near Me" please click here.
This article was printing in the March/April issue of Rethink Monthly magazine (issue #6).
Filed under Featured Articles, Music Reviews, Reviews
Tagged as Fiction Family, Fleet Foxes, free mp3, Jon Foreman, Review, Sean Watkins, Sufjan Stevens, The Welcome Wagon
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Today's WOW: Honesty is STILL the best policy!
I have a new goal to do a WOW (Wild on Wonder) Wednesday each week. The dictionary defines wonder as including, "marvel, awe, admiration, ponder, meditate, and to be thunderstruck"!
My WOW word for today is honesty. It's one of the "top ten" from Exodus 20:16 NIV: "You shall not give false testimony against your neighbor." I interpret that as no false testimony to anyone. Honesty is part of our soul (Mark 8:36), our character and integrity.
I would rather tell the truth, it's easier to remember! And I would also rather be hurt by the truth than "murdered" by a lie.
Stepfamilies need honesty within family members and co-parenting becomes more civil and trustworthy when parents and stepparents make a commitment to be honest and open. Children need to be coached and disciplined why honesty will enhance their adult lives and relationships.


text:
Orthodontium pallens är en bladmossart som beskrevs av Brotherus 1903. Orthodontium pallens ingår i släktet Orthodontium och familjen Bryaceae. Inga underarter finns listade i Catalogue of Life.

Källor

Egentliga bladmossor
pallens


My first experience with tacos happened soon after a Jack in the Box fast food restaurant opened in my home town of Brentwood, NY in the 1960s. That was one of the first fast food restaurants in the town, and was unique because it had a drive-thru—a real novelty at the time. They also had this strange menu item called "tacos."
Today, I shudder to think of the tacos served at the place. The shells were crisp, but the meat within them soaked them to the point where they were more chewy rather than crunchy. They had meat, taco sauce, shredded lettuce, and a (tiny) bit of cheese in them. For a kid in elementary school who never tasted tacos before, they were wonderful.
It wasn't until I was in high school that I had tacos from elsewhere. Taco Bell had a place in Centereach on Middle Country Road, and their tacos didn't have the sauce in them. Instead, they had packets of sauce that you could put on your tacos if you wanted. At first, I wasn't particularly thrilled with those tacos, but they eventually grew on me, and provided a counterpoint for the ones from Jack in the Box.
When I moved to Miami, FL, one of the things I noticed was that there were many, many places to find tacos. There were chains, there were small tacquerias run as Mom and Pop places, and there were Mexican restaurants.
My favorite chain in Miami was called Taco Viva, which offered over a half dozen different taco sauces, ranging from mild to "El Scorcho." The tacos here were fresher than the ones I had in New York, and they became a regular staple of my diet. Sandra appreciated the fact that they gave her a choice so that she didn't have to endure the El Scorcho that I tended to choose for myself.
It was also in Miami that I ventured to my first Mexican Restaurant—a place called El Torito in The Falls shopping center in southwest Miami. The Falls was built in the early 1980s and is an open-air mall with impeccable landscaping (with, of course, waterfalls). I went to El Torito with a few friends. My only experience with Mexican food, up until that first visit, was the tacos. El Torito introduced me to enchiladas, burritos, chimichangas and the other wonderful Mexican food items that I have since come to enjoy.
Back to the theme of this entry, though, I found that the tacos at El Torito were different than the fast food versions that I expected. Instead of using ground beef, their tacos were stuffed—actually, overstuffed—with shredded beef. Fresh lettuce, tomato, and cheese rounded out the taco, and there was salsa at the table if you wanted to add it to the tacos. Yum!
I remember a business trip I took to San Diego where there was a Mexican restaurant between the hotel and the convention center where the trade show I was presenting at. I popped over to that restaurant for lunch one day, and ordered a few tacos. The tacos I received were massively overstuffed with tasty ground beef and fresh vegetables—probably the best taco I ever had anywhere (too bad I can't remember the name of the restaurant... sorry!).
Believe it or not, I never actually tried to make tacos myself until I moved up north to New Hampshire. I found it a bit tricky to fold a corn tortilla to that familiar U-shape, but I kept persisting at it until I came up with something that wasn't too misshapen.
It wasn't until the kids were around, and we started a tradition we called "roll your owns" for a taco meal. I browned some ground meat and added taco seasonings and spices. While I cooked, Sandra and the kids would prepare lettuce, onions, shredded cheese, green onions, tomatoes, and cilantro onto plates. We had some salsa and other toppings such as sour cream put in bowls as well. Once the meat was cooked, I put it into a bowl, and then rinsed and dried the frying panso I could put it back on the burner, add about an inch of vegetable oile, and then I would start cooking the tortillas.
I'd cook each taco, one at a time and each made to order. In our family, the "mediums" were the most requested, since they offered a good compromise of bendability and crispness. Tostadas were also liked because they seemed to hold the most fillings (just pile it on!). Occasionally, a hard taco would be requested, and the soft tacos were almost never requested.
When everybody had their fill of tacos, I would cut the remaining corn tortillas into wedges and fried them. The chips and remaining salad ingredients, along with some salsa would be combined into a taco salad leaving no leftovers to have to worry about.


Crimes against persons are defined as are those whose victims are always individuals. Homicide, sexual assault, robbery and assault are examples. Crimes against children, elderly and disabled fall under crimes against persons. A detective follows up on all reports of child abuse that are received via the Texas Department of Family and Protective Services (DFPS).
Detectives normal working hours are Monday-Friday 8AM-5PM. Please call the non-emergency line at 512-753-2108 and listen for the option that best caters to your needs.


Welcome... to Blogtobia. : A sleeeeepy smile!
I'm with her. I'm ready to pass out... I love DMB, but I'm soooo glad I skipped this show this time.
Early day tomorrow... And long weekend ahead!
Vegas Sunday and Monday can't come soon enough... I'm out of gas and am ready to pass the eff out!!


It takes many volunteers, generous people and city support to keep operating our first class museum. The most rewarding aspect of volunteering is hearing the many positive comments from visitors who are impressed with the "big city museum" in Seymour. We were pleased to add several new exhibits this year and will continue to utilize the latest technology to help tell our story.
In addition to preserving area history and making it available to the public the Seymour Community Historical Society strives to continue to build our oral history and pictorial archive. In this issue of the Seymour History Bulletin you will enjoy a brief early history of the canning factory, a colorful description of a one room school, a childhood adventure, and an interview with long time Seymour residents Clayton and Audrey Ebert.
Be sure to visit the museum between 10:00 and 1:30 on Saturday, December 2nd for the Christmas open house. This year's theme a "Magical Kids Christmas" features popular cartoon characters in a holiday setting. Janice Eick and her sisters Jean and Joan, have done an outstanding job decorating the museum for Christmas.
The second floor has been turned into a winter wonderland with numerous decorated trees and winter scenes reflecting popular books and cartoons Mr. and Mrs. Santa Claus will be on hand to greet visitors and distribute holiday cheer. The first 100 children will receive a free gift to unwrap courtesy of a generous donor. Consistent with the theme, children have the opportunity to play with the Santa train and participate in making holiday crafts. Hot chocolate and Christmas cookies add to the holiday cheer. This is an excellent opportunity to treat the children or grandchildren and tour the festive museum.


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Used in body placements on the neck, throat, and Thyroid for soothing energy - releaseing your voice.


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This page looks at a variety of ZIP code 47226 Indiana housing market data taken from the most recent 2020 American Community Survey census data. Housing units are structures such as a single family home, apartment community, mobile home park, public housing, etc. where a person or family live and live separately from other residents of the building. Figure 1 shows the total number of housing units for each city. 47226 depicts it has a Housing Units of 97 which is the smallest when sorted by housing units of all the other zip codes in the local area.
Figure 2 illustrates the housing density in the ZIP code 47226 housing market as measured by housing units per square land mile (includes single family homes, apartments, etc.) ZIP code 47226 depicts it has a Housing Density of 936.4 which is the most of all zip codes in the greater ZIP code 47226 region. Comparing housing density to the United States average of 38.9, ZIP code 47226 is considerably bigger. Also, in contrast to the state of Indiana, housing density of 80.6, ZIP code 47226 is very much bigger.
In Figure 4, ZIP code 47226 area change in the number of housing units and is a forward gauge (along with population change) for any potential housing shortage. ZIP code 47226 shows it has a Housing Unit Change of -1.0% which is the second smallest when ranked by change in the housing units of all the other zip codes in the area. The zip code with the highest change in the housing units in the area is 47234 which depicts a housing units of 7.5% ( quite a bit bigger). Comparing change in the housing units to the United States average of 5.7%, ZIP code 47226 is about the same size. Also, in comparison with the state of Indiana, change in the housing units of 3.3%, ZIP code 47226 is about the same size.
Figure 5 shows the percentage of rental property based on that they are occupied by renters as a percent of the total number of households in the community (including homes, apartments, etc.) ZIP code 47226 depicts it has a Renter Percent of 19.3% which is the third most renter percent of all other zip codes in the greater ZIP code 47226 region. Figure 6 illustrates the total number of housing units that are occupied by owners. it has a Owner Percent of 80.7% which is less than most other zip codes in the greater region.
Looking at the housing data provided in Figure 7, the average ZIP code 47226 home price is illustrated for this community and a useful analysis of affordable housing. 47226 indicates it has a Median Home Value of $74,500 which is the smallest when ranked by median home price of all the other zip codes in the greater region. The zip code with the highest median home price in the area is 47203 which shows a home price of $171,600 (approximately 2.3 times bigger).
Figure 9 provides the frequency distribution of home prices for the area and is useful for understanding affordable housing fund. ZIP code 47226 has one of the largest proportions of home price worth less than $50,000 at 42% of the total and is ranked #2. The only larger zip code being 47280 with 51%.
Median owner costs for the real estate market are shown in Figure 10 and include the costs associated with any mortgage, utility expenses, insurance, and other miscellaneous costs. ZIP code 47226 depicts it has a Median Owner Cost of $570 which is the second smallest in order of median ownership cost of all the other zip codes in the local area. Figure 11 shows the median amount of cost as a percent of total household income for people who own homes in the ZIP code 47226 metro area. it has a Owner Cost as % of HH Income of 11% which is the second smallest when sorted by cost as a percent of household income of all the other zip codes in the greater region.
The next chart, Figure 12, provides a comparison chart of the median home cost as a percent of a median worker take home earnings and is thus a valuable measure of affordable housing. ZIP code 47226 shows it has a Median Home Value as Percent of Median Earnings of 200% which is the second smallest in order of median home value as a percent of median worker earnings of all the other zip codes in the local area.
Figure 14 depicts the median cost of housing for owners with also have a mortgages (versus those who do not have a mortgage because mortgage cost is included.) ZIP code 47226 shows it has a Median Owner Costs-With Mortgage of $950 which is the smallest as measured by median housing cost of all the other zip codes in the metro area. Figure 15 is a chart that shows the median housing costs for owners who do not have mortgages (and therefore the cost of home ownership does not include mortgage cost.) it has a Median Owner Costs-Without Mortgage of $372 which is less than most other zip codes in the metropolitan area.
Figure 16 shows the distribution in total housing cost for owners of property (so not renters.) This cost includes mortgages, lines of credit interest, utilities, taxes, insurance, etc. ZIP code 47226 has one of the largest proportions of owner cost less than $300 at 30% of the total and is ranked #2. The only larger zip code being 47280 with 79%. Second, it has the second smallest when ranked by owner cost less than $300 of all the other zip codes in the metro area as measured by owner cost between $500 and $700 at 15% of the total.
Next shown in Figure 17 is the housing cost as a percent of household income for people who own their homes and have a mortgages (thus the cost of financing the home is included.) ZIP code 47226 depicts it has a % of Income Owner Costs-With Mortgage of 14% which is the smallest when ranked by cost as a percent of household income of all the other zip codes in the local area. The zip code with the highest cost as a percent of household income in the area is 47280 which depicts a cost as a percent of household income of 21% (48.9% larger). Housing cost as a percent of household income for owners who do not have a mortgage is shown in Figure 18. This analysis can be useful for understanding the affordable housing for home ownership excluding any financing cost in the area shown. ZIP code 47226 depicts it has a % of Income Owner Costs-No Mortgage of 9% which is the third most of all other zip codes in the greater region. The zip code with the highest cost as a percent of household income in the area is 46124 which shows a cost as a percent of household income of 13% (45.6% larger).
Figure 19 looks at the cost of rent for rental property using the percent of total household income which is a valuable measure of financial health for the area. (The higher the proportion of rent payments to total household income is a sign of greater financial stress. Also, rent can be covered by rent assistance and rent assistance programs in the form of rent assistance.) ZIP code 47226 has one of the largest proportions of rent as a percent of income is less than 10 pct at 62% of the total and is ranked #2. The only larger zip code being 47234 with 100%.
Figure 20 shows the total housing cost for both home owners and apartment community renters in the area. ZIP code 47226 has the smallest proportion of housing cost between $500 and $700 at 20% of the total.
Figure 22 shows the percentage of renters who pay for utilities in ZIP code 47226 Indiana. This is calculated as the percent of renters who pay separately for utilities versus the people who have utilities included as part of amenities. ZIP code 47226 has the largest proportion of pay extra for utilities at 38% of the total and is ranked #1.
The analysis in Figure 25 shows the detailed distribution of owned homes by mortgage status. 47226 has the largest proportion of with mortgage at 19% of the total and is ranked #1. Second, it has the largest proportion of 2nd mortgage at 19% of the total and is ranked #1. Third, it has the smallest proportion of both 2nd mortgage and heloc at 31% of the total. Also, it has the largest proportion of no 2nd mortgage and no heloc at 49% of the total and is ranked #1.
Figure 26 shows the proportion of houses with a mortgage versus those without a mortgage. ZIP code 47226 has the largest proportion of houses with mortgages at 49% of the total and is ranked #1.
Figure 28 shows the household size for families living in the area and it has a Family size of 4.1 which is the second most family members per housing unit of all the zip codes in the greater ZIP code 47226 region. The zip code with the highest family members per housing unit in the area is 47280 which depicts a family members per housing unit of 4.3 (only about 3.6% larger). Comparing family members per housing unit to the United States average of 3.3, ZIP code 47226 is 24.3% larger. Also, benchmarked against the state of Indiana, family members per housing unit of 3.2, ZIP code 47226 is 28.8% larger.
Figure 29 show the median number of rooms in a typical home for each location in this area. it has a Median Number of Rooms of 5.6 which is the second smallest when ranked by average number of rooms in a house of all the other zip codes in the metro area. The zip code with the highest average number of rooms in a house in the area is 47244 which shows an average number of rooms in a house of 6.5 (16.1% larger). Figure 30 shows, for the average house in each location, the median year that a house was built. This can be useful for understanding the relative age of one neighborhood versus another for a real estate investor. it has a Median Year Built of 1957 which is the second smallest in terms of year built of all the other zip codes in the greater region. The zip code with the highest year built in the area is 47203 which depicts a year built of 1977 ( only slightly larger).
Figure 31 looks at the distribution of housing units by the median age that the homes were built. has the percentage of homes built between 2010 to 2013 the second smallest in order of homes built in 2014 or later of all the other zip codes in the greater region at 2% of the total. Second, it has one of the largest proportions of homes built between 1980 to 1989 at 21% of the total and is ranked #3. Only #2 47203 (22%), and #1 47246 (22%) are larger. Third, it has the second smallest when sorted by homes built in 2014 or later of all the other zip codes in the local area when sorted by homes built between 1970 to 1979 at 5% of the total. Also, it has the largest proportion of homes built between 1960 to 1969 at 30% of the total and is ranked #1. In addition, it has the smallest proportion of homes built between 1950 to 1959 at 2% of the total. Furthermore, it has one of the largest proportions of homes built between 1940 to 1949 at 27% of the total and is ranked #3. Only #2 47234 (27%), and #1 47244 (44%) are larger.
Figure 32 shows the difference in the number of housing units based on whether they are occupied by owners versus occupied by renters. has the smallest proportion of owner housing units at 16 of the total.
Figure 33 shows the difference in the number of housing units based on whether they are occupied by owners or renters. it has the largest proportion of 2 units at 6% of the total and is ranked #1. Second, it has the largest proportion of 50 or more units at 16% of the total and is ranked #1.
Figure 34 shows the median value of homes broken down by the median year that the homes were built. it has one of the largest proportions of value of homes built 2000 to 2009 at $181,300 of the total and is ranked #2. The only larger zip code being 47203 with $189,000. Second, it has in the middle range of other zip codes in the greater region when sorted by value of homes built 1980 to 1989 at $48,000 of the total. Third, it has one of the largest proportions of value of homes built 1960 to 1969 at $132,500 of the total and is ranked #2. The only larger zip code being 47203 with $135,100. Also, it has the second smallest as measured by value of homes built 2014 or later of all the other zip codes in the greater region in order of value of homes built 1940 to 1949 at $63,800 of the total.
The next two charts show both the average household size of homeowners versus the average household size of renters. Starting with Figure 36 we see the household size of homeowners for ZIP code 47226 residents. it has a Owner-Household Size of 3.1 which is the second most of all the zip codes in the surrounding region. The zip code with the highest homeowner household size in the area is 47280 which shows a homeowner household size of 3.4 (10.7% larger).
Figure 37 shows the household size for renters. ZIP code 47226 depicts it has a Renter-Household Size of 3.3 which is the second most of all the zip codes in the greater region. The zip code with the highest renter household size in the area is 47280 which shows a renter household sizes of 4.4 (33.8% larger). Figure 38 shows the year that people who own homes moved into this region. it has the largest proportion of owners moved in 2017 or later at 46% of the total and is ranked #1. Second, it has the second smallest when sorted by owners moved in 2017 or later of all the other zip codes in the greater region in terms of owners moved in 2015 to 2016 at 8% of the total. Third, it has the smallest proportion of owners moved in 2010 to 2014 at 18% of the total. Also, it has the smallest proportion of owners moved in 2000 to 2009 at 6% of the total. In addition, it has one of the largest proportions of owners moved in 1990 to 1999 at 23% of the total and is ranked #2. The only larger zip code being 47246 with 24%. Figure 39 shows the year that people who rent moved into the area. ZIP code 47226 has the smallest proportion of renters moved in 2010 to 2014 at 13% of the total.
Figure 40 compares the median year that home owners moved into their home. it has a Owner Median Year Moved In of 2003 which is the third most median year that a home owner moved in of all other zip codes in the greater ZIP code 47226 region. Figure 41 compares the median year that renters moved into their home. ZIP code 47226 depicts it has a Renter Median Year Moved In of 2018 which is more than all other zip codes in the greater ZIP code 47226 region.
Figure 42 shows the frequency distribution of various types of energy sources used for homes in the community. it has one of the largest proportions of home using bottled, tank, or lp gas at 34% of the total and is ranked #3. Only #2 47244 (38%), and #1 47246 (44%) are larger.
Zip code 47226, Indiana Housing Data
Figure 1: 47226, IN Area Total Housing Units
Figure 2: 47226, IN Housing Density (Houses per Sq. Mile)
Figure 5: Rental Homes in 47226, IN
Figure 6: Owned Homes in 47226, IN
Figure 7: 47226, IN Median Home Prices
Figure 8: 47226, IN Median Monthly Rent Amounts
Figure 9: 47226, IN Home Price Distribution
Figure 10: 47226, IN Median Monthly Owner Cost
Figure 14: 47226, IN Median Monthly Owner Cost with Mortgage
Figure 15: 47226, IN Median Monthly Owner Cost without Mortgage
Figure 16: Distribution of Monthly Owner Costs in 47226, IN
Figure 19: 47226, IN Rent as a percent of Household Income
Figure 20: Monthly Housing Cost for Owners or Renters in 47226, IN
Figure 21: 47226, IN Median Annual Real Estate Taxes Paid
Figure 22: 47226, IN Utilities Included with amenities or Excluded in Rent
Figure 23: 47226, IN Monthly Median Rent Rates
Figure 24: 47226, IN Monthly Median Rent Rates by Size of Rental in Bedrooms
Figure 25: 47226, IN Detailed Mortgage Status
Figure 26: 47226, IN Houses With vs. Without a Mortgage
Figure 27: Average Household Size in 47226, IN
Figure 28: Average Family Size in 47226, IN
Figure 30: 47226, IN Median Year House Built
Figure 31: 47226, IN Year that House Built Distribution
Figure 32: Number of Owners vs. Renters in 47226, IN and Area
Figure 33: 47226, IN Area Housing Types
Figure 34: 47226, IN Median Home Value By Year Structure Built
Figure 35: Occupied and Vacant Housing units in 47226, IN
Figure 37: 47226, IN Renter Household Size
Figure 42: 47226, IN Fuel Used to Heat Home
Figure 44: 47226, IN Population in Group Quarters
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Q: Formulas breaking upon Row Insertions and Deletions How can we tell Excel to keep relative references no matter what (after insertions and deletions)?
I have a simple checkbook-like sheet.
Column C for Refunds, D for Expenses (entered with a negative) and column E for a Running Balance.
Currently using the following formula for the Running Balance
=E16+C17+D17

like so

which however breaks all the time, like after certain row insertions and I have to copy paste the formula to fix column E.
The formula breaks like so:

To reproduce the issue
select row 17, then control-shift-+, Excel changes the formula at E18 to
E16+C18+D18

and not
E17+C18+D18

I hacked the following (A)
=SUM(INDIRECT("E"&ROW()-1),INDIRECT("C"&ROW()),INDIRECT("D"&ROW()))

But it still fails upon row insertion
(for instance, select row 17, then control-shift-+, Excel 2010 reverts to inserting in, the now blank row 17, with the following formula at E17
=E16+C17+D17  (instead of using my formula (A) )
How can I fix this and make it less error prone?
Thank you

A: This formula seems to work for me:
=INDEX(E:E,ROW()-1)+INDEX(C:C,ROW())+INDEX(D:D,ROW())

As you can see by adding the row the formula stayed the same and referenced the correct number.

A: What about:
=Indirect("E16")+Indirect("C17")+Indirect("D17")?

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