Tamelander, C. Wexels Riser and the anonymous reviewers. “
“Bays are subject to various kinds of human pressure, such as domestic sewage, industrial waste, harbours, aquaculture and the activities of electric power plants. Increased anthropogenic input to embayments has resulted in their severe eutrophication. Primary production in such enriched environments has increased and phytoplankton communities have changed

(Oviatt et al., 1989, Spatharis et al., 2007 and Wang et al., 2009). The composition and structure of zooplankton are also significantly different, with the proportion of small zooplankton increasing in heavily eutrophic bays (Uye, 1994, Uye et al., 1998, Park and Marshall, 2000 and Chang et al., 2009). Daya Bay is a semi-enclosed bay on the northern continental shelf of the South China Sea (Figure 1a, see p. 585). In the last 30 years, the nutrient structure has become eutrophic mainly as a result of marine see more aquaculture and waste drainage from land (Wang et al., 2006, Wang et al., 2009 and Wu and Wang, 2007). The Daya Bay Nuclear Power Plant (DNPP) has been operative in the south-west part of Daya Bay since 1993. These changes have affected the bay’s ecological environment. The growth of small diatoms has accelerated and become predominant in the aquaculture areas (Wang et al. 2009). The rise in temperature caused by thermal discharge

from the power plant has favoured dinoflagellates over diatoms learn more (Li et al. 2011). The zooplankton in Daya Bay has been investigated since the 1980s (Xu 1989). However, little is known about the influence

of these human activities on the zooplankton at the scale of short- and long-term changes. The objective of this study was to attempt to understand the short-term variations of the zooplankton community and the influence of environmental factors on their distribution pattern. We hypothesised that the zooplankton community differed among the three areas (the outflow of nuclear power plant ONPP, the marine cage-culture area MCCA and the adjacent unpolluted waters UW). To test this hypothesis, we analysed the zooplankton species composition, its spatial and temporal variations, and environmental factors by the use of a high-frequency sampling strategy during a short period in Dapeng Cove (located in the south-west of Daya Bay). It was also expected Phospholipase D1 that the study would provide insight into the long-term variation of zooplankton in Daya Bay. Dapeng Cove (Figure 1a), was selected as the survey area because it is greatly affected by human activities. The DNPP is on the north shore of the cove. Fish, shrimp and shellfish aquaculture have been well developed there since 1985, and a cage-cultured fishery is situated in its inner waters, which results in highly eutrophic conditions. Six sampling stations were located in Dapeng Cove (Figure 1b). Stations 1 and 2 (S1 and S2) were at the water intake and outflow of the DNPP respectively.

At the present time we still do not have appropriate numerical Bioactive Compound Library cost data characterizing the accuracy of current and/or forecast estimates

of other structural and functional parameters of marine ecosystems, in particular the concentration of chlorophyll a, which would support the usefulness of such coupling. Even so, this usefulness is being confirmed by the preliminary results of analyses, the results of which will be published at a later date. The work done so far in the SatBałtyk project confirms the usefulness of satellite systems for the comprehensive and effective monitoring of the current state of the marine environment, and also to a large degree for the forecasting of a whole range of natural phenomena taking place in Baltic waters and in the atmosphere above, including the monitoring of the water’s purity and the extent of its eutrophication. These satellite systems enable the production of maps of spatial distributions of many state parameters of this environment, as well as certain state parameters and optical properties of the atmosphere, surface

temperatures in different basins and hence surface currents and upwelling events, the range and direct spread of river waters in the Baltic, water transparency and the optical properties of the sea, the depth of the euphotic zone, the radiation balance at the sea surface and in the upper layers of the atmosphere, the intensity of UV Protein tyrosine phosphatase radiation PFI-2 in vivo over the sea and coastal areas, the distributions of irradiance energy useful for photosynthesis PAR, the concentration of chlorophyll and other pigments in the water, the primary production of organic matter and the photosynthetically released oxygen in

the sea, as well as the extents of phytoplankton blooms (including toxic cyanobacteria). It is also possible to determine a range of biological parameters characterizing, among other things, the condition of marine life, in particular algae and their physiological and phytophysiological parameters like the maximum assimilation number, the factor of non-photosynthetic pigments, the efficiency of photosynthesis at different depths, and the maximum quantum yield of photosynthesis in water of a given trophicity. Specific examples of many of these physical, chemical and biological parameters characterizing the sea-atmosphere system and marine ecosystems and the processes taking place in them will be described and discussed in Part 2 of this series of articles (see Woźniak et al. (2011) in this issue). This will show distribution maps of some of these parameters in the Baltic Sea, produced using the algorithms of the SatBałtyk Operational System. These examples provide an ample illustration of the merits and potential uses of these algorithms. “
“The present article (Part 2) brings to a close the summary of the results of the first year and a half of SatBałtyk’s implementation.

The task group on eutrophication of check details the Marine Strategy Framework Directive [15] emphasized the advantages of using remote sensing for monitoring eutrophication. Eutrophication is defined here as ‘a process driven by enrichment of water by nutrients, especially compounds of nitrogen and/or phosphorus, leading to: increased growth, primary production

and biomass of algae; changes in the balance of organisms; and water quality degradation. The consequences of eutrophication are undesirable if they appreciably degrade ecosystem health and/or the sustainable provision of goods and services’ [15]. In Sweden, the use of remote sensing in coastal management is still in its infancy. The aim of this case study is to illustrate how remote sensing and bio-optics can be incorporated in integrated coastal zone management of the Baltic Sea in general, and of Himmerfjärden (Fig. 2) in particular. Furthermore, it is described how optical parameters can be used as indicators for ecosystem health and eutrophication. In the following sections

the reader will first be introduced to the area of investigation; Himmerfjärden bay, and the basics of bio-optics and remote sensing using Himmerfjärden as a case study. The work has been published in a more technical form in selleck various remote sensing articles [2], [16] and [17] and here relevant concepts are interpreted in relation to the WFD. After this, the development of an operational remote sensing system for the coastal zone is described. The system was developed in close collaboration with end-users, and the process of SPICOSA stakeholder involvement in system development

Megestrol Acetate is shown. Himmerfjärden is a fjord-like bay situated in the Southern Stockholm Archipelago, just south of 60° N, opening into the Baltic Sea (Fig. 2). With a mean depth of about 17 m Himmerfjärden is rather shallow and consists of a sequence of basins divided by several sills. The bay and its adjacent waters have been well studied for many years, in part because of concern about nutrient enrichment by urban waste water [18] and [19]. Due to the low freshwater input (flushing rate 0.025 d−1) and the presence of the sills Himmerfjärden has a weak circulation, and as observed generally in the Baltic Sea, there is virtually no tidal influence. The local catchment area consists of 57% forest, 33% land, 4% lakes and 5% urban areas [21]. Himmerfjärden is subject to frequently occurring blooms of filamentous cyanobacteria during summer, dominated by Aphanizomenon sp. and Pseudanabaena limnetica [20], as well as occasional surface blooms of Nodularia spumigena. Blooms of N. spumigena, however, are more frequent and more intense in the open Baltic Sea, where they may cover large areas that can be monitored from space. The development of large surface accumulations of cyanobacteria are usually related to persistent warm weather during summer, induced during the development of a seasonal thermocline. In particular, N.

The observed enrichment of these minor variants suggests that they may encode for marginal reductions in susceptibility to sofosbuvir that cannot be measured with current in vitro systems.

It is possible that there is ongoing low-level replication selleck chemicals llc during treatment in some patients, perhaps owing to the presence of the HCC lesions, resulting in an enrichment of these mutants relative to wild-type and then transient detection at relapse/recurrence before wild-type dominates again. The clinical significance of the appearance of these minor variants remains to be determined. Because of the small size of this study, any conclusions must be considered preliminary in nature and require further evaluation in larger studies. Extrapolation of these results to all patients with HCV awaiting liver transplant is limited by the fact that the population studied comprised patients with compensated or mildly decompensated liver disease undergoing transplantation for hepatocellular carcinoma. At the time the study was designed,

the safety of sofosbuvir had not been evaluated in decompensated liver disease, and we therefore chose patients with a diagnosis of hepatocellular carcinoma meeting the Milan criteria so that the efficacy of the regimen for preventing post-transplant recurrence could be evaluated in patients with lower MELD scores, but who would be expected to undergo liver transplantation within 1 year. Studies of sofosbuvir regimens in patients with more advanced disease pretransplant are underway. The lack of a control arm to define PLX4032 efficacy and tolerability of the regimen was another shortcoming, although ascertainment bias

is unlikely given the universal recurrence of HCV in untreated patients. The majority of patients in this study had an undetectable viral load at the Arachidonate 15-lipoxygenase time of transplant and achieved pTVR. However, nonresponse and relapse were observed in a substantial proportion of patients, which led to re-infection of the allograft. It is unknown whether continuation of sofosbuvir and ribavirin through the post-transplant period in patients with a shorter duration of virologic suppression before transplantation could reduce rates of recurrence. Alternatively, higher rates of pTVR may be possible through the addition of another direct-acting antiviral to pretransplant sofosbuvir and ribavirin. In conclusion, therapy with sofosbuvir and ribavirin before liver transplantation prevented the recurrence of HCV infection after transplantation in 70% of patients who had undetectable levels of HCV RNA before transplantation. Given the burden of disease owing to HCV recurrence post-transplantation—the increased morbidity, mortality, and costs—these results provide hope for patients in need. The authors thank the patients and their families, the investigators, and site personnel.

5 Both diseases share varying degrees of esophageal eosinophilia and some authors suggest that mucosal injury caused by acid reflux may allow swallowed allergens to penetrate esophageal mucosa causing mild eosinophilia.5 and 7 Gastroesophageal reflux disease is actually the most common cause of eosinophilic infiltration

of the esophagus. However, GERD-related infiltrates tend to be less dense and the greatest number is in the distal esophagus, whereas the dense infiltrates of eosinophilic esophagitis are seen throughout the esophagus.5 and 7 Because of this possible overlap, the diagnosis of eosinophilic esophagitis should be made after acid reflux has been treated or excluded.1 and 5 Before we considered eosinophilic esophagitis

diagnosis and performed esophageal biopsies, our patient tried a trial with pump proton inhibitor at maximum doses VX-809 manufacturer and a pH monitoring excluded pathologic gastroesophageal reflux. Therefore, R428 nmr our patient met all criteria for definitive diagnosis of eosinophilic esophagitis: clinical symptoms, compatible histology and lack of responsiveness to high-dose pump proton inhibitor with normal pH monitoring of the distal esophagus. Because many patients with eosinophilic esophagitis have atopic disease, a complete evaluation for dietary and inhaled allergens by an experienced allergist is recommended. Although we could not find any correlation between our patient’s reflux symptoms and exposition to pollens or grass, avoidance of allergens may be helpful in some patients.1 Large-scale studies in adults have not been conducted. There is no consensus regarding the treatment of eosinophilic esophagitis. In adults, food allergy is less responsible and treatment with topical steroids has lead to remission of symptoms and normalization of hitopathology.1 and 8 Treatment involves spraying Acetophenone and actuation of fluticasone from an inhaler into the mouth and having the patient swallow. Patients should

be instructed to avoid food and liquids for at least 30 minutes after use.1 and 9 A trial of a proton pump inhibitor at maximum doses for at least 8 weeks is also recommended.1 Swallowed fluticasone was very effective in our patient, leading to complete clinical remission after one month of treatment. After six months of treatment, there were no eosinophils in esophageal biopsies. In patients whose symptoms do not improve with fluticasone, several other medications may be tried like systemic corticosteroids, cromolyn sodium and montelukast. A recent open-label trial with mepolizumab, a humanized monoclonal antibody to human interleukin 5, improved clinical symptoms in patients with refractory eosinophilic esophagitis.10 Esophageal stenosis may complicate esophageal esophagitis.

Along this salinity gradient, the basin of the Gulf of Riga has one of the lowest macrovegetation species diversities. The Gulf of Riga has a surface area of 17913 km2, a volume of 406 km3, a maximum depth of 52 m and an average depth of 23 m. The average salinity in the gulf is 5.6. Outside the straits, the currents in the practically tideless Selleck MEK inhibitor Estonian coastal sea are meteorologically driven and generally neither persistent nor strong (Suursaar et al.

2012). Because of the semienclosed configuration of the study area and the presence of some shallow bays exposed to the direction of the strongest expected storm winds, the sea level variability range is up to 4 m in Pärnu Bay and about 3 m elsewhere in the gulf (Jaagus & Suursaar 2013). As a result of the small area of the gulf (140 × 150 km2), significant wave heights (Hs) may reach

4 m when a storm wind blows from the direction of the longest fetch for a particular location (Suursaar et al. 2012). Long, relatively calm periods are interspersed with occasional wind and wave storms without a noteworthy swell-component. In general, the swash climate associated with low-energy dissipative beaches (with wide surf zones and flat beach profiles) supports an abundant coastal life (Lastra et al. selleck chemical 2006). As the beach type changes towards reflective conditions with short surf zones, coarse bottom substrates and steep slopes, the increasingly inhospitable swash climate gradually excludes sensitive species. The specific study locations at Kõiguste (58°22′N, 22°59′E), Sõmeri (58°21′N, 23°44′E) and Orajõe (57°57′N, 24°23′E; Figure 1) are predominantly low-energy beaches with low-lying hypsometric curves. The bottom substrate varies between sandy and morainic (Martin 1999). According to earlier studies, the three areas showed slightly different patterns of phytobenthic communities. While the Kõiguste area was characterised by high coverage and biomass, the other areas had a lower coverage and biomass of benthic vegetation (Martin 2000). According to previous studies, the most frequent

species were filamentous algae such as Ceramium tenuicorne (Kützing) Waern, Polysiphonia fucoides (Hudson) Greville, Pilayella Teicoplanin littoralis (Linnaeus) Kjellman and Battersia arctica (Harvey) Draisma, Prud’homme & H. Kawai in the Gulf of Riga ( Martin 1999). Recently, the filamentous red alga P. fucoides occurred most frequently and with high coverage in all the areas studied ( Kersen 2012). Sampling of the seabed phytobenthic community was carried out in three areas (Kõiguste, Sõmeri and Orajõe) in the northern Gulf of Riga (Figure 1) in May, July and September 2011. In each area, macrophyta were observed along three parallel transects placed perpendicularly to the shoreline with a distance of 500 m between the transects. The length of the transect was 2–4 km depending on the area. The depth intervals of the sampling sites along the transects were 1–1.5 m.

Initial assays were performed in haemagglutination and haemagglutination inhibition

assays where sheep red blood cells were coupled to purified FLC from individual patients (Ling et al., 1977). Ascites cells were adapted to in vitro culture, and were expanded in a mini-perm bioreactor. Bioreactor supernatants (MiniPerm, Sarstedt) containing anti-FLC mAbs were purified using protein G or SpA chromatography (GE Healthcare). Purified mAb collections were diluted this website 1/100 and quantified by spectrophotometry (Eppendorf) at 280 nm for protein concentration, with 1.43 extinction coefficient (Hay et al., 2002). Initially, anti-FLC mAbs were selected based on reactivity with all κ or λ FLC antigens in a panel of different BJ proteins, and minimal cross-reactivity to a panel of purified whole immunoglobulins. Specificity was established by covalently coupling mAbs to Luminex® Xmap® beads (Bio-Rad, UK) and quantifying polyclonal light chains from dithiothreitol treated immunoglobulin infusate

(Gammagard Liquid), which was then reduced and/or acetylated and separated on a G100 column in the presence of proprionic acid, and quantified using Freelite™. In addition, specificity was established on the Luminex® against: (a) a panel of serum samples from patients with elevated polyclonal light chains and myeloma; and, (b) a panel of urine samples containing BJ CB-839 proteins. From this process, two anti-κ (BUCIS Baricitinib 01 and BUCIS 04) and two anti-λ (BUCIS 03 and BUCIS 09) FLC mAbs were chosen for further development and initial validation in the mAb assay (Serascience, UK). Individual urines containing a high level of BJ protein were centrifuged and 0.2 μm filtered. Purity assessment was conducted by SDS Page and those identified as showing a single band of monomeric FLC and/or single band of dimeric FLC, indicating that there were no other proteins visible, were dialysed against deionised water with several changes of water. Each preparation was passed over activated charcoal, concentrated by vacuum dialysis, and freeze-dried on a vacuum dryer and protein

stored at 4 °C. Calibrator material was made by combining four sources of purified BJ λ protein and five sources of BJ κ protein. 105 mg of each FLC protein was dissolved in 15 mL saline, overnight at 4 °C. The supernatants were 0.2 μm filtered before measuring the concentration by spectrophotometry at 280 Å at a dilution of 1/100 and extinction coefficient of 11.8 (Hay et al., 2002). Equal amounts of each BJ κ or λ protein were combined and the volumes of the two preparations were adjusted with sterile PBS to a concentration of 7 mg/mL. Sodium azide was added from a 0.2 μm filtered preparation of 9.9% w/v in deionised water to give a final concentration of 0.099%. The preparations were aliquoted into 1 mL volume and stored at − 80 °C.

The seasonal pattern in Fig. 8(a) and (b) also shows that the ASW and the MWDW both reside for several months beneath the FIS, potentially affecting basal melting far inside

the cavity. The MWDW, entering the cavity at the main sill in Fig. 8(b), is advected along topographic (f/Hf/H) contours further into the cavity, appearing as a warmer bottom layer (green) at the southernmost end of the cross-section in Fig. 8(a), and eventually causes melting of deep ice of Jutulstraumen. The evolution of the ASW, entering in the upper part of the cavity in Fig. 8(a), is shown by the thickened and more stratified layer of cold ISW (magenta) at the southern end in Fig. 8(b). A water mass analysis (not shown) reveals that the buoyant upper Autophagy signaling pathway inhibitor portion of this ISW layer is formed by surface water which entered the cavity during the previous

summer and has expended its available heat for melting. Thus, our simulations confirm the hypothesis of Hattermann et al. (2012) that ASW can travel far into the ice shelf cavity, after initially being subducted beneath the ice front. An overview of the horizontal current strength and direction is presented in the lower panels of Fig. 8. A dominant feature of the sub-ice shelf circulation is the presence of counter-rotating, topographically constrained flows in the upper and lower water column of the central basin. At depth, the model shows a clockwise flow steered by the bottom topography, while in the upper part of the water column a counter-clockwise flow along ice PLX4032 mw draft contours is observed. We find that the different circulation patterns in the upper and lower parts of the cavity are a direct result of the enhanced stratification due to the presence of ASW. This can be seen by comparing the results from the ANN-100 experiment (Fig. 8(c) and (e)) to the circulation in the initial simulation (Fig. 8(d) and

(f)), which uses the WIN-100 forcing where no ASW is included in the model. In contrast to the vertically sheared currents described MRIP above, the constant winter scenario shows a narrow but fast-flowing, topographically steered barotropic jet, with much larger current speeds in the upper part of the water column than observed in the ANN-100 experiment. Also the seasonal variability in the ANN-100 experiment (not shown) reveals stronger and more barotropic sub-shelf currents near the ice base during late winter and spring when the upper ocean stratification is weak. The analysis of the ANN-100 experiment thus, reveals several effects of ASW on the cavity ventilation and associated basal melting. In particular, the pronounced seasonality of the MWDW inflow at depth, which occurs in the absence of any variability of the wind forcing, is an interesting result implying a direct link between upper ocean hydrographic conditions and the deep ocean heat fluxes. In fact, without ASW in the model, no MWDW enters the cavity, as can be seen from the last six months of the constant winter initial simulation in Fig. 5(a).

Die 2002 in den USA empfohlene Tagesdosis (RDA) für Zink, die vom National Research Council herausgegeben wurde [155], ist mithilfe dieser Methode abgeleitet worden und zusammen mit den Empfehlungen von Komitees anderer Länder in Tabelle 6 aufgelistet. Die Bioverfügbarkeit find more ist nur bei der Empfehlung der Weltgesundheitsorganisation (WHO) [155], nicht aber bei den anderen Empfehlungen, durch Korrekturen berücksichtigt. Weiterhin ist unklar, welcher VK für den Absolutbedarf angesetzt werden sollte. Dies ist wichtig, denn je niedriger der VK ist, desto niedriger liegt auch

die berechnete RDA. Die Environmental Protection Agency der USA [168] verwendete Daten von Yadrick et al. [169] über den Effekt von Zink auf die Absorption von Kupfer und Eisen als Grundlage für die Berechnung eines „lowest-observed adverse-effect level, LOAEL“. Unter der Annahme, dass 15 bzw. 30% Zink bioverfügbar sind, wurden RfDs von 1,66 und 0,83 mg/kg/Tag errechnet [170]. Für Zinksupplemente, die zu 95% absorbierbar sind, wurde eine RfD von 0,25 mg/kg/Tag errechnet.

Dieser Wert entspricht 17,5 mg Zink bei einem Mann mit einem Körpergewicht von 70 kg selleck chemical und 15 mg bei einer Frau mit einem Körpergewicht von 60 kg. Dies steht ganz offensichtlich im Widerspruch zu Zinksupplementen, die bis zu 50 mg Zink oder gar noch mehr enthalten. Eine RfD von 0,33 mg/kg/Tag hat den Zweck, Personen zu schützen, nicht aber, Toxizität zu prognostizieren. Daher ist die RfD ähnlich wie bzw. niedriger als die RDA für Zink filipin von 1989 [150] und niedriger als der vorläufige Vorschlag zum Zinkbedarf von der WHO bei einer Bioverfügbarkeit von 15% [171]. Zusammengenommen scheinen diese Daten anzudeuten, dass es keinen AROI für 95% der Bevölkerung gibt, also für eine Gruppe, die in Bezug auf Alter, Geschlecht und andere Charakteristika, von denen angenommen wird, dass sie den Bedarf beeinflussen, homogen ist, aber nicht demographisch oder kulturell gesehen. Das Problem wird u. U. noch weiter

kompliziert durch Unterschiede zwischen Individuen hinsichtlich der Sensitivität, sowohl was Defizienz als auch was Toxizität betrifft. Möglicherweise sollten sich Schätzungen eines LOAEL und einer Obergrenze für Zink auf das Zn:Cu-Verhältnis beziehen. Der Zusammenhang zwischen mit der Nahrung zugeführtem Zink, Kupfer und Protein (Tabelle 3) legt einen LOAEL für Zink von 13,7 mg nahe, wenn die mit der Nahrung zugeführte Kupfermenge 0,83 mg beträgt (Zn:Cu-Verhältnis = 16,5 auf Gewicht und 16,1 auf Molarität bezogen). Die Obergrenze würde durch die Kupferaufnahme bestimmt. Z. B. wäre bei einer Aufnahme von 1,5 mg Kupfer und 13,7 mg Zink (Zn:Cu-Verhältnis = 9,1) die aufgenommene Menge Zink sicher und adäquat.

02–1.03). Further analyses for interactions demonstrated different time trends for different ages and different levels of comorbidity for nonvariceal hemorrhage (likelihood ratio tests for interactions of both age and comorbidity with year, P < .001) but not for variceal hemorrhage (year and age, P = .29; year and

comorbidity, P = .67). Consequently, the age-specific stratum average annual changes in odds of mortality for nonvariceal hemorrhage are presented in Table 4. The annual improvement in odds of mortality was minimal for those presenting 80 years and older compared with all the other age groups. Further stratifying the model by age and comorbidity ( Table 5) demonstrated that, within each age-specific stratum, the improvement in mortality did not differ by the level of comorbidity. Therefore, the final model of a linear trend selleck in 28-day

mortality for nonvariceal hemorrhage is the model shown in Table 4, with confounding by comorbidity adjusted for by logistic regression and effect modification demonstrated by stratifying the results by age. The final model of BMN 673 purchase a linear trend in 28-day mortality for variceal hemorrhage demonstrated only confounding by both comorbidity and age with no effect modification. The failure of previous studies to demonstrate improvements in mortality after upper gastrointestinal hemorrhage at the population level calls into question the value of therapeutic changes that are of proven benefit to individuals. In an increasingly challenging economic environment, clinicians will need to be able to demonstrate that increased therapeutic expenditure really does bring benefits. That 28-day mortality for equivalent patients, following hospital admission for both nonvariceal and variceal upper gastrointestinal hemorrhage, has reduced by 2% and 3%, respectively, year on year in England over the period 1999 to 2007 is therefore of great importance. The demonstration that this can be shown through the analysis of routinely collected data may be of great value in the assessment of other conditions. When, as in this case, a study’s findings differ from the previous literature, we must ask whether this is because the

current or previous studies were in error or whether they are in reality observing different things. The data source chosen for our study from provides key advantages. The study is the largest to date of mortality after hospital admission for gastrointestinal hemorrhage and therefore has power to demonstrate trends that would be missed in smaller studies. It also has power to demonstrate variations in trends between subgroups of the population such as the smaller reduction in mortality in those over 80 years old with nonvariceal hemorrhage. The provision within the dataset of information on the previously suggested confounders of age and comorbidity is also of great benefit and has allowed us to clearly show and correct for this confounding.