Computed tomographic angiography measures of coronary plaque in clinical trials: opportunities and considerations to accelerate drug translation.

Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but new pharmacologic therapies require increasingly large and expensive cardiovascular outcome trials to assess their potential impact on MACE and to obtain regulatory approval. For many disease areas, nearly a half of drugs are approved by the U.S. Food & Drug Administration based on beneficial effects on surrogate endpoints. For cardiovascular disease, only low-density lipoprotein cholesterol and blood pressure are approved as surrogates for cardiovascular disease. Valid surrogates of CAD are urgently needed to facilitate robust evaluation of novel, beneficial treatments and inspire investment. Fortunately, advances in non-invasive imaging offer new opportunity for accelerating CAD drug development. Coronary computed tomography angiography (CCTA) is the most advanced candidate, with the ability to measure accurately and reproducibly characterize the underlying causal disease itself. Indeed, favourable changes in plaque burden have been shown to be associated with improved outcomes, and CCTA may have a unique role as an effective surrogate endpoint for therapies that are designed to improve CAD outcomes. CCTA also has the potential to de-risk clinical endpoint-based trials both financially and by enrichment of participants at higher likelihood of MACE. Furthermore, total non-calcified, and high-risk plaque volume, and their change over time, provide a causally linked measure of coronary artery disease which is inextricably linked to MACE, and represents a robust surrogate imaging biomarker with potential to be endorsed by regulatory authorities. Global consensus on specific imaging endpoints and protocols for optimal clinical trial design is essential as we work towards a rigorous, sustainable and staged pathway for new CAD therapies.

Is water quality in British rivers "better than at any time since the end of the Industrial Revolution"?

We explore the oft-repeated claim that river water quality in Great Britain is "better now than at any time since the Industrial Revolution". We review available data and ancillary evidence for seven different categories of water pollutants: (i) biochemical oxygen demand (BOD) and ammonia; (ii) heavy metals; (iii) sewage-associated organic pollutants (including hormone-like substances, personal care product and pharmaceutical compounds); (iv) macronutrients (nitrogen and phosphorus); (v) pesticides; (vi) acid deposition and (vii) other variables, including natural organic matter and pathogenic micro-organisms. With a few exceptions, observed data are scarce before 1970. However, we can speculate about some of the major water quality pressures which have existed before that. Point-source pollutants are likely to have increased with population growth, increased connection rates to sewerage and industrialisation, although the increased provision of wastewater treatment during the 20th century will have mitigated this to some extent. From 1940 to the 1990s, pressures from nutrients and pesticides associated with agricultural intensification have increased in many areas. In parallel, there was an increase in synthetic organic compounds with a "down-the-drain" disposal pathway. The 1990s saw general reductions in mean concentrations of metals, BOD and ammonia (driven by the EU Urban Waste Water Treatment Directive), a levelling out of nitrate concentrations (driven by the EU Nitrate Directive), a decrease in phosphate loads from both point-and diffuse-sources and some recovery from catchment acidification. The current picture is mixed: water quality in many rivers downstream of urban centres has improved in sanitary terms but not with respect to emerging contaminants, while river quality in catchments with intensive agriculture is likely to remain worse now than before the 1960s. Water quality is still unacceptably poor in some water bodies. This is often a consequence of multiple stressors which need to be better-identified and prioritised to enable continued recovery.

Nitrate in United kingdom rivers: policy and its outcomes since 1970.

Modern conventional farming provides Western Europe and North America with reliable, high quality, and relatively cheap supplies of food and fiber, increasingly viewed as a potential source of fuel. One of the costs is continued widespread pollution of rivers and groundwater-predominantly by nutrients. In 1970, in both the United States and UK, farming was focused on maximizing yield and management practices were rapidly modernizing. Little attention was paid to the external impacts of farming. In 2010, diffuse pollution from agriculture is being seriously addressed by both voluntary and statutory means in an attempt to balance environmental costs with the continued benefits of agricultural production. In this paper we consider long-term changes in the concentration and flux of nitrate in five rural UK rivers to demonstrate the impact of agricultural intensification and subsequent policies to reduce diffuse pollution on river water quality between 1970 and 2010.

Long-term monitoring of river water nitrate: how much data do we need?

Long records of river water quality are invaluable for helping to understand the biogeochemistry of hydrological systems. They allow relationships to be established between changes in water quality (including seasonal cycles, episodic responses and long-term trends) and potential drivers, such as climatic forcing or human activity; they can act as a stimulus for process-oriented experimental research; they can be used to help to make predictions about future temporal and spatial patterns; and they can help to guide management options to mitigate water pollution. In this paper we present the case in favour of maintaining some long records of river water nitrate concentration at "benchmark" sites, in terms of enhancing process understanding and identifying system lags. Many long-term time series of nitrate concentration data share similar features including a pronounced seasonality characterised by a clear winter maximum, an upward trend in the post-war period followed by a levelling off, or even a decline in the last 20 years, and unusually high concentrations following drought years. Concentrations in any one year are often dependent on conditions in previous years; relationships can be established between concentrations and hydrological drivers (such as rainfall) with different lag periods which can yield information about supply or transport limitations to nitrate transfers. The interpretation of any record is dependent on its length: short records have a high potential for misinterpretation. Often, the value of long records only becomes apparent when analysed in retrospect, perhaps yielding insight into processes and phenomena for which the data collection programme was not originally designed. We, therefore, urge monitoring agencies to devise a strategy for maintaining long records--at least for a few benchmark stations.

An assessment of the risk to surface water ecosystems of groundwater P in the UK and Ireland.

A good quantitative understanding of phosphorus (P) delivery is essential in the design of management strategies to prevent eutrophication of terrestrial freshwaters. Most research to date has focussed on surface and near-surface hydrological pathways, under the common assumption that little P leaches to groundwater. Here we present an analysis of national patterns of groundwater phosphate concentrations in England and Wales, Scotland, and the Republic of Ireland, which shows that many groundwater bodies have median P concentrations above ecologically significant thresholds for freshwaters. The potential risk to receptor ecosystems of high observed groundwater P concentrations will depend on (1) whether the observed groundwater P concentrations are above the natural background; (2) the influence of local hydrogeological settings (pathways) on the likelihood of significant P transfers to the receptor; (3) the sensitivity of the receptor to P; and, (4) the relative magnitude of P transfers from groundwater compared to other P sources. Our research suggests that, although there is often a high degree of uncertainty in many of these factors, groundwater has the potential to trigger and/or maintain eutrophication under certain scenarios: the assumption of groundwater contribution to river flows as a ubiquitous source of dilution for P-rich surface runoff must therefore be questioned. Given the regulatory importance of P concentrations in triggering ecological quality thresholds, there is an urgent need for detailed monitoring and research to characterise the extent and magnitude of different groundwater P sources, the likelihood for P transformation and/or storage along aquifer-hyporheic zone flow paths and to identify the subsequent risk to receptor ecosystems.

Temporal and spatial analysis of nitrate concentrations from the Frome and Piddle catchments in Dorset (UK) for water years 1978 to 2007: evidence for nitrate breakthrough?

This paper analyses time series of nitrate concentration for 35 sites throughout the Frome and Piddle catchments in southern England for the period 1978--2007. The Piddle catchment lies wholly within the Chalk aquifer in its upper reaches, whereas the headwaters of the Frome are a mixture of Chalk and other lithologies; both rivers flow across Palaeogene sands and clays in their lower reaches, before discharging into Poole Harbour. At each site sources of observed variation arise from differences between sample month (seasonality) and year (underlying trend). Considering water year mean concentrations, there is a strong and highly significant positive correlation with year for all but two sites. The annual rate of increase tends to be higher in the Piddle than the Frome, and in both catchments the annual rate of increase tends to decrease downstream; both these effects relate to the degree of groundwater influence. In addition to the strong upward trend, there is also a clear seasonal cycle in nitrate concentration at most sites; amplitude generally increases downstream. Laying aside the assumption of linearity, solute breakthrough curves (S-curves) are fitted to 34 of the 36 nitrate time series. Results show that application of S-curves is an appropriate description of changes in annual mean concentrations over time and provides improvements over linear models in most cases. The interpretation of rising nitrate concentrations in these groundwater-dominated catchments moves from a statistical to a hydrological process base, providing valuable insight into lowland catchment function.

Reference urodynamic values for stress incontinent women.

OBJECTIVE: To determine reference urodynamic values for preoperative urodynamic studies in women undergoing surgery for pure or predominant stress urinary incontinence (SUI). MATERIALS AND METHODS: Six hundred fifty-five women with pure or predominant SUI were enrolled in a multicenter surgical trial and were randomized to undergo a Burch or autologous fascia sling procedure as part of the Urinary Incontinence Treatment Network (UITN) Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr). Preoperative free uroflowmetry, filling cystometry, and pressure flow studies were performed in all women using a standardized research protocol and standardized urodynamic interpretation guidelines. We define the normal range of urodynamic values in this population as the values that encompass 95% of the results. RESULTS: In 655 women undergoing filling cystometry in the standing position, baseline vesical and abdominal pressures were between 12 and 60 cm H(2)O. The upper limit of detrusor pressure increase during bladder filling to maximum cystometric capacity was 16 cm H(2)O. Ten percent of women who qualified for stress incontinence surgery with a positive cough stress test on physical exam did not demonstrate urodynamic stress incontinence (USI) and less than 10% of subjects in this study demonstrated detrusor overactivity. CONCLUSIONS: Results from a large cohort of women with SUI are now available for quantitative plausibility assessments or as reference values when interpreting urodynamic studies.

Positron emission tomography/computed tomography imaging for the detection of recurrent ovarian and fallopian tube carcinoma: a retrospective review.

PURPOSE: Imaging modalities to evaluate ovarian/fallopian tube cancer patients for recurrence are limited. Positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound lack the sensitivity to consistently detect recurrence or measurable disease in these patients. A new technique combines PET and CT (PET/CT) images to identify increased metabolic activity and to locate that signal with improved anatomic specificity. The objective of this study is to compare PET/CT, CT, and histologic findings in patients with recurrent ovarian/fallopian tube cancers. METHODS: Retrospective chart review of eight patients with primary ovarian (n = 6) or fallopian tube (n = 2) cancer was performed. All eight patients underwent initial cytoreductive surgery. Five patients initially received chemotherapy, one received radioactive phosphorus ((32)P), one received tamoxifen, and one received no therapy. Seven of eight patients had a suspected recurrence based on clinical examination, elevated CA-125 level, and/or abnormal CT findings; one patient requested a PET/CT. Histologic findings from surgery were correlated with PET/CT and CT findings. RESULTS: All eight patients had positive histology, and of these, seven patients had a negative CT and five patients had lesions that were correctly identified by PET/CT. CONCLUSIONS: Five of the eight (62%) patients had recurrent disease based on correlative histology with a positive PET/CT and a negative CT. These preliminary findings suggest that combined PET/CT may be an effective means of identifying patients with recurrent ovarian/fallopian tube cancer. Such patients could potentially proceed to salvage treatment and avoid the morbidity and expense of surgical assessment. Pilot studies comparing CT, PET, PET/CT, and histologic findings are underway.