Probabilistic models to describe the dynamics of migrating microbial communities

In all but the most sterile environments bacteria will reside in fluid being transported through conduits and some of these will attach and grow as biofilms on the conduit walls. The concentration and diversity of bacteria in the fluid at the point of delivery will be a mix of those when it entered the conduit and those that have become entrained into the flow due to seeding from biofilms. Examples include fluids through conduits such as drinking water pipe networks, endotracheal tubes, catheters and ventilation systems. Here we present two probabilistic models to describe changes in the composition of bulk fluid microbial communities as they are transported through a conduit whilst exposed to biofilm communities. The first (discrete) model simulates absolute numbers of individual cells, whereas the other (continuous) model simulates the relative abundance of taxa in the bulk fluid. The discrete model is founded on a birth-death process whereby the community changes one individual at a time and the numbers of cells in the system can vary. The continuous model is a stochastic differential equation derived from the discrete model and can also accommodate changes in the carrying capacity of the bulk fluid. These models provide a novel Lagrangian framework to investigate and predict the dynamics of migrating microbial communities. In this paper we compare the two models, discuss their merits, possible applications and present simulation results in the context of drinking water distribution systems. Our results provide novel insight into the effects of stochastic dynamics on the composition of non-stationary microbial communities that are exposed to biofilms and provides a new avenue for modelling microbial dynamics in systems where fluids are being transported

Prevalence of left ventricular diastolic dysfunction in a general population

BACKGROUND: Because the process of myocardial remodelling starts before the onset of symptoms, recent heart failure (HF) guidelines place special emphasis on the detection of subclinical left ventricular (LV) systolic and diastolic dysfunction and the timely identification of risk factors for HF. Our goal was to describe the prevalence and determinants (risk factors) of LV diastolic dysfunction in a general population and to compare the amino terminal probrain natriuretic peptide level across groups with and without diastolic dysfunction. METHODS AND RESULTS: In a randomly recruited population sample (n=539; 50.5% women; mean age, 52.5 years), we measured early and late diastolic peak velocities of mitral inflow (E and A), pulmonary vein flow by pulsed-wave Doppler, and the mitral annular velocities (Ea and Aa) at 4 sites by tissue Doppler imaging. A healthy subsample of 239 subjects (mean age, 43.7 years) provided age-specific cutoff limits for normal E/A and E/Ea ratios and the differences in duration between the mitral A and the reverse pulmonary vein flows during atrial systole (DeltaAd-ARd). The number of subjects in diastolic dysfunction groups 1 (impaired relaxation), 2 (elevated LV end-diastolic filling pressure), and 3 (elevated E/Ea and abnormally low E/A) were 53 (9.8%), 76 (14.1%), and 18 (3.4%), respectively. We used Delta(Ad<ARd+10) to confirm possible elevation of LV filling pressures in group 2. Compared with subjects with normal diastolic function (n=392, 72.7%), group 1 (209 versus 251 pmol/L; P=0.015) and group 2 (209 versus 275 pmol/L; P=0.0003) but not group 3 (209 versus 224 pmol/L; P=0.65) had a significantly higher adjusted NT-probrain natriuretic peptide. Higher age, body mass index, heart rate, systolic blood pressure, serum insulin, and creatinine were significantly associated with a higher risk of LV diastolic dysfunction. CONCLUSIONS: The overall prevalence of LV diastolic dysfunction in a random sample of a general population, as estimated from echocardiographic measurements, was as high as 27.3%

Circulating biomarkers predicting longitudinal changes in left ventricular structure and function in a general population

Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C‐terminal telopeptide, matrix metalloproteinase‐1) and high‐sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (−14.2%) and increase in E/e′ ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, −14.2%; C‐terminal telopeptide, −16.4%; P≤0.029). An increase in E/e′ ratio over time was borderline associated with lower matrix metalloproteinase‐1 (+9.8%) and lower matrix metalloproteinase‐1/tissue inhibitor of metalloproteinase‐1 ratio (+11.9%; P≤0.041). Higher high‐sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow‐up (P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation

Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds

BACKGROUND: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. METHODS: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). RESULTS: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. CONCLUSIONS: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%

Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds

BACKGROUND: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. METHODS: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). RESULTS: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. CONCLUSIONS: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%

Ambulatory Monitoring Uncorrected for Placebo Overestimates Long-term Antihypertensive Action

Abstract &apos;This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and anlbulatory BP measurement. Older patients (260 years, n=337) with isolated systolic hypertension by conventional sphygrnomanometry at the clinic were rando~nized to placebo or active treatment consisting of nitrendipine (10 to 40 mgid), with the possil~le addition oF enalapril (5 10 20 mgid) ;~nd/or hydrochlorothiazide (12.5 Lo 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175186 mm Hg and 24-hour and daytimc ;~mbulatory BPs averaged 148180 and 154185 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.717.0 mm Hg and 24-hour and daytime BPs by 10.514.5 and 9.714.3 mm Hg, respectively (P&lt;.001 for all). However, clinic (9.811.6 mm Hg), 24-hour (2.11 1.1 nini Hg), and daytime (2.911.0 mm Hg) BPs decreased also during placebo (P&lt;.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12. 915.4, 8.313.4, and 6.813.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (R.05). Changes during placebo in hourly systolic and diastolic BP means amounled to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-tern~ BP changes observed during active treatrnent may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration. (Hypertension. lYY6;27[part 1]:414-420.) Key IYords blood pressure monitoring, ambulatory antihypertensive therapy clinical trials blood pressure monitoring placebo T he SYST-EUR Trial is a double-blind, placebocontrolled outcome trial in older patients with isolated systolic hypertension that the European Working Party on High Blood Pressure in the Elderly is currently conducting in Western and Eastern Europe and in 1srael.l Presently, the 3000 patients originally planned lor have been randomized. In accordance with current clinical practice,2 only conventional sphygmomanometric BP readings by an auscultating observer determine a patient&apos;s eligibility for randomization and guide the stepwise adjustments of treatment during the double-blind phase of the trial. &apos; In addition to conventional sphygmomanometry, arnbulatory BP monitoring is increasingly used in clinical trials to evaluate the magnitude and duration of the BP-lowering action of antihypertensive agents. SYST-EUR centers can opt to monitor their patients in an attempt to evaluate whether the ambulatory BP, over ancl above the clinic BP, is helplul in predicting cardiovascular events.&apos; This article builds on the data collected so Tar in the SYST-EUR Trial1 and contrasts the effects Received August 25, 1995; first decision September 18, 1995; revision accepted October 31, 1995. Correspondence to Jan A. Staessen, MD, PhD, Klinisch Labo-~;ltol.iuni Ilypertensie, Inwendige Geneeskunde-Cardiologie, U Z Gaslhuisberg, Herestraat 49, Belgiu~n. 0 L996 American Heart Association, Inc. of antihypertensive treatment and placebo as assessed by conventional sphygmomanometry and ambulatory monitoring. 11 extends the findings o l a previous article that was limited to the placebo arm of the triaL4 Methods Study Design &apos;The protocol of the SYST-EUR Trial has been published elsewhere.&apos; It was approved by the Ethics Committee of the Faculty of Medicine at the University of Leuven as well as by the institutional review committees of all participating centers. Patients were eligible (I) if they were at least 60 years old; (2) if, on a placebo during the run-in phase, their sitting SBP ranged from 160 to 219 mm Hg with a DBP below 95 mm Hg; (3) if their standing SBP was 140 mm Hg or higher; and (4) if, after having been informed, they voluntarily consented to be enrolled. The BP criteria for entry rested on the averages of six silting and six standing readings, ie, two in each position at three baseline visits I month apart. Eligil~le patients were stratifed by sex and the presence versus absence of cardiovascular complications and were randomized to double-blind treatment with active medication or placebo. Aclive treatment consisted of nitrendipine BP and Other Measurements SYST-EUR centers opting to take part in ambulatory rnonitoring were asked to perform recordings at baseline, at 6 and 12 months, and annually thereafter? Validated5.Wonitors were programmed to obtain measurements at intervals not greater than 30 minutes. The conventional BP corresponding to each ambulatory recording was the average of the two readings with patients in the sitting position obtained at the nearest clinic visit. The patients were interviewed at baseline and follow-up concerliing their smoking habits, habitual alcohol intake, and activities of daily l i~i n g .~,~ In addition, the serum activity of yglulanlyllranspeptidase was determined as an index of alcohol intake.&quot; Analysis of the Diurnal BP Profile If the ambulatory recordings were longer than 24 hours, only the first 24 hours was used for analysis. Recordiligs were excluded whenever the available readings constituted less than 80% of those program~netl or covered less than 22 consecutive hours. I&apos;he editing criterial&quot;.ll considered for tlelelion of readings from the recordings were (1) SBP&lt;DBP, (2) SBP &gt;240 or &lt;40 mm Hg, (3) DBP &gt;I40 or &lt;40 mm Hg, (4) pulse rate &gt;l50 or &lt;40 beats per minute, and (5) pulse pressure &lt;10% of SBP. The 24-hour, daytime, and nighltime pressures and hourly BP means were weighted for the time between consecutive readings. l 2 Daytime was from I0 AM to 8 PM and nighttime from mitlnight to 6 AM. These dcfnitions of daytime ancl nighttime have been used in previous s t~d i e s~~&apos;~~~ and exclude the transition periods in the morning and evening during which BP changes rapidly. The awake and sleeping periods were determined from diary cards kept by the patients on recording days.7 Statistical Analysis Database management and statistical analyses were performed with the SAS software (SAS Institute Inc). Statistical methods included Student&apos;s t test and linear regression analysis. Diurnal BP profiles, drawn from hourly BP means, were contrasted by repeated measures ANOVA,I4 considering as main effects treatment allocation (active versus placebo) and time of day. For establishment of whether the antihypertensive action was steady over 24 hours, the model also tested for a treatment-time interaction. The net treatment effect, sometimes referred to as the double delta of BP,&quot; was calculated by subtracting the mean change from baseline during placebo from the corresponding change during active treatment. The 95% confidence limits about the net treatment effect showed the times during the day when the BP reduction was significant. The reproducibility of duplicate measurements was studied by the Bland and Altman technique.lh For co~nparison of the reproducibility of various BP measurements, the repeatability coefficients were expressed as a percentage of nearly maximal variation, ie. the interval encompassing four times the S D of the averaged tluplicate measurements. Results Data Available for Analysis On May 15, 1995, 407 patients had their ambulatory BP recorded during the run-in phase of the trial and at least once after randomization. In 174 of these patients, duplicate recordings had been obtained at baseline. After patients with incomplete recordings were excluded, these numbers were 337 and 118, respectively. The 792 ambulatory recordings included in the present analysis comprised a total of 51 960 single BP readings, of which only 1.5% complied with at least one of the criteria considered for editing. In 501 recordings (63%), no single reading met the editing criteria. Because editing did not influence the results, only analyses based on unedited recordings are presented. Patient Characteristics at Randomization The patients allocated to placebo (n=169) and active treatment (n= 168) had the same characteristics at randomization. They comprised 142 men and 195 women. Cardiovascular complications were present in 94 patients. Of the 337 patients, 167 had been treated during the 6 months before they were considered for entry into the trial, 30 with diuretics, 19 with P-blockers, 21 with converting enzyme inhibitors, 33 with calcium entry blockers, and 64 with various other drugs or with a combination of several antihypertensive agents. Previous antihypertensive treatment was usually discontinued l month before the first run-in visit during placebo. The median time interval between the latter visit and randomization was 76 days (range, 36 to 300) in the previously treated patients and 70 days (range, 20 to 300) in the other patients. In all 337 patients, age averaged 7026 (5SD) years (range, 60 to 100). Body mass index was 26.153.3 kg/m2 in men and 26.554.0 kg/m2 in women. SBP at the clinic averaged 175k 12 mm Hg (range, 160 to 217) and DBP 8656 mm Hg (range, 49 to 94). The corresponding 24-hour pressures were 1485 16 mm Hg (range, 1 10 to 202) and 8059 lnln Hg (range, 58 to 138), respectively. Daytime versus awake and nighttime versus sleeping SBP and DBP did no1 differ Reproducibility of Clinic and Ambulatory Pressures at Baseline In 118 patients, ambulatory monitoring had been repeated during the run-in phase of the trial at a median interval of 33 days (range, 7 to 127). Reproducibility of the clinic pressure was studied by contrasting the averages of the two readings obtained with patients in the sitting position at two outpatient visits. Group means of the clinic and ambulatory pressures could be reproduced without significant changes in their values, except for the 24-hour, daytime, and awake SBP, which decreased (1-&apos;&lt;.05) by approximately 2 mm Hg, and for the awake DBP, which decreased (Pc.05) by 1 mm Hg Treatment Effects on Clinic and Ambulatory Pressures Follow-up averaged 13 months (median) (range, 4 to 30). Of the 337 paticnts, 310 remained on the lirst-line medication, ie, nitrendipine (n=151; daily dose, 27212 mg) or matching placebo (n=159). At the follow-up visit. second-and third-line medications had been started in 49 (1427 mg) and 21 (2226 mg) patients on active treatment and in 84 and 47 patients on placebo. Active treatment decreased the clinic and ambulatory SBP and DBP, but also during placebo these pressures tended to decline Over the follow-up period, no significant changes occurred in the patients&apos; body weight (mean change?SD, -0.123.4 kg), smoking habits (-0.625.3 g tobacco per day), alcohol intake (-0.625.3 gld), serum y-glutamyltranspeptidase activity ([email protected]%), and score for the activities of daily living (median change, 0; range, -5 to +I). Modifications over the follow-up period in these lifestyle measures and previous antihypertensive treatment were not correlated with the decrease in the ambulatory BP values in the placebo group. The changes in body weight constituted the only possible exception because they tended to be positively associated with the changes in the 24-hour DBP (regression coefficientkSE, 0.2920.16 mm tiglkg; P=.07) and in the daytime (0.3820.20 mm Hgl kg, P=.OS) and nighttime (0.3520.19 mm Hglkg, P=.07) DBPs. Treatment Effects on Diurnal BP Profiles At both baseline and follow-up, time of day was a significant (P&lt;.001) source of BP variation. At baseline, treatment allocation (!&apos;=.g6 for SBP, P=.39 for DBP) as well as the interaction terms between treatment and time of day were not significant (P=.75 and .40, respectively). These results confirmed that during the run-in phase, the diurnal BP profiles were superimposable in the two treatment arms of the trial At follow-up, active treatment shifted (P&lt;.001) the diurnal BP profile downward Disparity Between Clinic and Ambulatory Measurements At baseline, the correlation coefficients between the clinic and daytime measurements were .46 for SBP and .39 for DBP. The corresponding correlation coefficients at fc&gt;llow-up were .57 and .49 in the placebo group and .32 and .35 during active treatment (PC.001 for all correlations). Clinic SBP was on all occasions higher (P&lt;.001) than daytime SBP, ie, 21215 mm Hg at baseline, 14k17 mm Hg during placebo at follow-up, and 9&amp;19 mm Hg during active treatment. In contrast, the mean differences between the clinic and daytime DBPs were small, averaging l + 10 mm Hg at baseline as well as during placebo at follow-up and -2+ 11 mm Hg during active treatment. 1)iscussion After approximately 1 year, the net separation in the clinic pressure between the two treatment groups aver- Approximately one third of the patients enrolled in the SYST-EUR Trial undergo ambulatory monitoring, in addition to conventional sphygmomanometry. The net separation between the two treatment arms after a median follow-up of approximately 1 year was considerably smaller for the ambulatory than for the clinic pressures, ie, 4.912.0 mm Hg less for the 24-hour pressures and 6.112.2 mm Hg less for the daytime pressures. Thus, the differentiation in the clinic pressures between the two treatment groups was 55%/59% larger than observed for the 24-hour pressures and 90%/69% larger than for the daytime pressures. The currently prevails that ambulatory recordings more closely reflect a patient&apos;s habitual BP level than the few readings taken by an auscultating observer in the stressful hospital e n v i r~n m e n t .~~-~T h e present study therefore suggests that the true BP responses in a long-term randomized clinical trial are overestimated by conventional sphygmomanometry by as much as 50% to 90%. The latter estimate is in agreement with a large meta-analysis of prospective observational studies in the field of hypertension.24 A correction for regression dilution bias was calculated by introducing the so-called usual BP, defined as an individual&apos;s average BP over several years. According to these ~alculations,2~ a 12 mm Hg difference in the baseline pressure was rescaled into a 7.5 mm Hg contrast in the usual pressure. Thus, BP measurements at a single occasion (baseline) were felt to inflate the gradient in the usual pressure by approximately 60%. Staessen et a1 Ambulatoly BP Monitoring During Placebo 417 BP measurements by conventional sphygmomanometry have guided patient recruitment and therapy in most clinical trials in the field of hypertension, including all outcome trials.2Wespite their track record, conventional BP readings are subject to the so-called placebo effect, often attributed to a gradual weakening of the alerting reaction22,23 and to a regression-to-the-mean phenomenon.2&quot;-29 If conventional and anlbulatory measurements are repeated within the same subjects, the latter are characterized by greater reprodu~ibility,2~~ attributable to the absence-of digit preferen~e,&quot;~ ob- server bias,&quot;) and the white coat reaction22,2&apos;.31 but foremost to the greater number of readings averaged for calculation of the ambulatorv v a l~e s . 3~ This was confirmed in the present study, in which the clinic pressures dui-ing the placebo run-in period showed higher repeatahilily cc~cficicnts, signirying lowcr intrainclividual reproducibility, than the 24-hour and daytime pressures. Debate continues over whether ambulatory BP measurements decrease during placebo. The intra-arterially measured an~bulatory pressure has been demonstrated to remain at the same level when hypertensive patients were put on a placebo for 6 weeks.&quot;klong simiiar lines, in a 6-week study with a noninvasive recording technique,&apos;4 the ambulatory pressure fell only slightly during the initial recording hours, such that the average BP over 24 hours stayed unaffected. On balance, most publications currently favor the view that the ambulatory pressure is not subject to a placebo e f f e~t . &apos; &quot; &apos; &quot;~~-~~. -7 &quot; -~~ HOWever, few long-term studies on this subject have been published. A previous SYST-EUR publication4 based on 112 patients and limited to the placebo arm of the trial showed that after a median follow-up of 1 year the clinic SUP fell by 6.6 mm tIg (P&lt;.001) and the 24-hour and daytime SBPs by 2.4 (P&lt;.05) and 2.6 mm Hg (P=.06), respectively. The corresponding decreases in DBP were smaller, averaging only 1.4 (P-.06), 1.1, and 0.7 mm Hg.4 These estimates were of the same order of magnitude as in the present analysis, in which, because of the larger number of patients, the changes during placebo in the clinic and 24-hour DBPs also reached a level of statistical significance. The decline in the ambulatory BP values, amounting to approximately 2 mm Hg, may seem trivial and negligible. However, in relative terms they represented 43%1 23%, 20%/24%, and 30%/23% of the corresponding reductions in the clinic, 24-hour, and daytime SBPs/DBPs during active treatment. As far as the clinic pressure is vations, eg, during placebo, cannot be refuted and is part of the established culture among trialists. If this rule is true for the clinic pressure, then in opposition to the prevailing view in the literat~re,~3.1&quot;2&quot;-29,&quot;3-4&quot;t also needs to be applied for the ambulatory pressure, of which a substantial fraction may be explained by placebo-like effects. This reasoning not only involves the average 24-hour and daytime pressures but also the hourly BP means, which represent the treatment effects through the whole day. In the present study, the decreases in the hourly BP values during placebo constituted up to 70% of what was observed during active treatment. In the present study, the reduction in the clinic SBP during placebo may have been influenced by the 160 mm Hg threshold used to select the patients and by a subsequent regression-to-the-mean phenomenon. However, other mechanisms are also likely to have been at play because decreases during placebo were observed in the clinic DBP, which in all patients was lower than 95 mm Hg, as well as in the ambulatory measurements, which were not used to select the patients. Familiarization with the hospital environment or the procedure of ambulatory monitoring could be examples of such mechanisms. In addition, the present analysis demonstrated that changes in lifestyle were unlikely to be involved to a major extent. The clinic SBP was 21 mm Hg higher than the daytime pressure at baseline but only 14 and 9 mm Hg higher at follow-up during placebo and active treatment, respectively. These findings suggest that the white coat effect wears off as time goes by. It may also be attenuated by antihypertensive treatment, which probably dampens the BP surges caused by sympathetic arousal to the Staesserz et a1 Ambulatory BP Monitoring During Placebo 419 observer measuring the BP. Furthermore, the decreases in the ambulatory measurements during placebo and active treatlncnt were proportional to the BP level a1 baseline. T h e regression equations derived in the present studv vredicted that the 24-hour SBP would decrease , . by only 3.0 mm H g during active treatment in patients whose 24-hour SBP at entry was 135 mm Hg, ie, the 95th percentile in normotensive s~b j e c t s .~~h~s , in agreement with a previous report,47 prescribing antihypertensive medications to patients with a high clinic but low ambulatory pressure would not result in a substantial reduction of the habitual BP through the day. T h e issue of whether ambulatory measurements need to be corrected for placebo is not without importance, as it inherently touches o n the design of clinical trials in the field of hypertension. Some experts4x feel that ambulatory monitoring eliminates only observer bias and expectation4&quot; and does not remove regression-to-the-mean and patient-related factors that contribute to the placebo effect. Other researchers defend the point of view that ambulatory monitoring would make control observations during placebo s u p e r f l~o u s .~~ If this were true, trials making use of the new technique could investigate antihypertensive interventions just by comparing the B P levels before and after therapy. T h e present findings suggest that the latter approach may lead t o a n overestimation of the true antihypertensive effect and should therefore be abandoned at least in long-term trials. A correction for placebo may even be warranted in shortterm trials because the reproducibility data in this study showed that after a median interval of 1 month the average 24-hour and daytime SBPs decreased during placebo by 1.8 and 2.4 mm Hg, respectively. Thus, clinical trials relying on ambulatory monitoring should adhere t o the same design standards as those making use of conventional sphygmomanometry. Despite theselimitations, ambulatory monitoring, compared with conventional B P readings, offers the advantage of providing information o n B P control through the whole day and makes it possible t o economize o n sample size in crossover but not parallel group trials.&quot

Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Background. The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase 2 dose-finding study of rostafuroxin, a digitoxygenin deivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. Methods. OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24 h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). Results. Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P=0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P=0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P=0.03) for systolic office BP; 0.70 mm Hg (P=0.08) for diastolic office BP; 0.36 mm Hg (P=0.49) for 24-h systolic BP; and 0.05 mm Hg (P=0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤=0.028), but carry-over effects were not significant (P≥=0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. Conclusions. In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. Trial Registration: NCT00415038 http://www.clinicaltrials.gov)

Considerations for reducing food system energy demand while scaling up urban agriculture

There is an increasing global interest in scaling up urban agriculture (UA) in its various forms, from private gardens to sophisticated commercial operations. Much of this interest is in the spirit of environmental protection, with reduced waste and transportation energy highlighted as some of the proposed benefits of UA; however, explicit consideration of energy and resource requirements needs to be made in order to realize these anticipated environmental benefits. A literature review is undertaken here to provide new insight into the energy implications of scaling up UA in cities in high-income countries, considering UA classification, direct/indirect energy pressures, and interactions with other components of the food–energy–water nexus. This is followed by an exploration of ways in which these cities can plan for the exploitation of waste flows for resource-efficient UA. Given that it is estimated that the food system contributes nearly 15% of total US energy demand, optimization of resource use in food production, distribution, consumption, and waste systems may have a significant energy impact. There are limited data available that quantify resource demand implications directly associated with UA systems, highlighting that the literature is not yet sufficiently robust to make universal claims on benefits. This letter explores energy demand from conventional resource inputs, various production systems, water/energy trade-offs, alternative irrigation, packaging materials, and transportation/supply chains to shed light on UA-focused research needs. By analyzing data and cases from the existing literature, we propose that gains in energy efficiency could be realized through the co-location of UA operations with waste streams (e.g. heat, CO2, greywater, wastewater, compost), potentially increasing yields and offsetting life cycle energy demands relative to conventional approaches. This begs a number of energy-focused UA research questions that explore the opportunities for integrating the variety of UA structures and technologies, so that they are better able to exploit these urban waste flows and achieve whole-system reductions in energy demand. Any planning approach to implement these must, as always, assess how context will influence the viability and value added from the promotion of UA

Interpretation and Visualization of Non-Linear Data Fusion in Kernel Space: Study on Metabolomic Characterization of Progression of Multiple Sclerosis

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Fusion of metabolomics and proteomics data for biomarkers discovery: case study on the experimental autoimmune encephalomyelitis

Contains fulltext : 91843.pdf (publisher's version ) (Open Access)12 p