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Background: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. Methods: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0–28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin–clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. Findings: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin–clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [non-inferiority

Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating a toxic syndrome that can be lethal if left untreated (Cannard, 2006). It is standard practice to treat Sarin (GB) intoxication with an oxime, an antimuscarinic such as atropine and an anticonvulsant. Three common oximes are available: HI-6, Pralidoxime (2-PAM) and Obidoxime (Obi), all possess a nucleophile that can break the NA-AChE covalent bond. However, each oxime's efficacy profile against various agents is different (Thiermann and Worek, 2018). In an effort to broaden therapeutic efficacy against a range of possible NA's, consideration should be given to the use of two oximes in combination. Using a guinea pig model, the first arm of this study was to determine the pharmacokinetics (PK) of HI-6 DMS, 2-PAM chloride and Obi chloride (at autoinjector equivalent doses) following intramuscular (i.m.) co-administration along with atropine to replicate either a single isometrically scaled dose (referred to in this study as a single autoinjector equivalent) of 2-PAM (and equimolar doses of Obi and HI-6) or double doses (referred to in this study as two autoinjector equivalents). The second arm of the study evaluated the efficacy of Obi and 2-PAM individually at a single or double autoinjector dose and also in combination against GB exposure. Pharmacokinetic profiles of each oxime were evaluated for both arms of the study and no significant change in parameters were reported. Improved cholinesterase reactivation was observed in a dose dependent manner with combined therapy showing similar reactivation to individual oximes alone at a two autoinjector equivalent dose. Seizure activity was reduced when combined oxime therapy was administered. This improvement was also reflected in the Racine seizure index score assigned at the end of the experimental period. To the best of our knowledge, this study is the first to evaluate and compare the pharmacokinetics of three oximes and the combination of two oximes (2-PAM and Obi) administered in naïve animals or those exposed to GB. Combined oxime therapy (Obi and 2-PAM) resulted in improved seizure control, increased cholinesterase reactivation peripherally and centrally and improved behavioral signs (Racine score). This study provides evidence that combination of oximes is effective, does not result in adverse events and that the pharmacokinetics of each oxime are not affected when administered in combination.

The endothelial glycocalyx is critically involved in vascular integrity and homeostasis, by regulating vascular permeability, regulating mechanotransduction, and reducing inflammation and coagulation. The turnover of the glycocalyx is dynamic to fine-tune these processes. This is in particular true for its main structural component, hyaluronan (HA). Degradation and shedding of the glycocalyx by enzymes, such as hyaluronidase 1 and hyaluronidase 2, are responsible for regulation of the glycocalyx thickness and hence access of circulating cells and factors to the endothelial cell membrane and its receptors. This degradation process will at the same time also allow for resynthesis and adaptive chemical modification of the glycocalyx. The (re)synthesis of HA is dependent on the availability of its sugar substrates, thus linking glycocalyx biology directly to cellular glucose metabolism. It is therefore of particular interest to consider the consequences of dysregulated cellular glucose in diabetes for glycocalyx biology and its implications for endothelial function. This review summarizes the metabolic regulation of endothelial glycocalyx HA and its potential as a therapeutic target in diabetic vascular complications.

Contains fulltext : 182393.pdf (Publisher’s version ) (Open Access) Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase. Four weeks of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage, with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6C(hi) monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the CD206(+)/Mac3(+) cell ratio, as an index of presence of anti-inflammatory macrophages, increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of IL-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy.

Background Cardiorespiratory fitness (CRF) is reduced in patients with stroke. It is unclear whether it is also reduced in patients with a transient ischemic attack (TIA) or minor stroke. We investigated the CRF in patients with a recent TIA or minor stroke and explored which determinants are associated with a lower fitness. Methods In 113 patients with a recent TIA or minor ischemic stroke (64 (SD = 10) years of age; 49 (IQR 27-86) days post TIA or stroke), the peak oxygen consumption (VO2peak) was determined in a symptom-limited ramp exercise test. Physical activity level, vascular risk factors, history of vascular or pulmonary disease, and stroke characteristics were recorded at inclusion and related to the VO2peak. Results Mean VO2peak was 22 mL/kg/min (SD = 6), which is the fifth percentile of age- and sex-related normative values. Increasing age and female sex were associated with a lower VO2peak (B (95% CI): per 10 years −2.57 mL/kg/min (−3.75; −1.40) and female sex −5.84 mL/kg/min (−8.06; −3.62)). Age- and sex-adjusted linear regression analyses showed that a history of cardiovascular disease and pulmonary disease was associated with a lower VO2peak. In addition, a lower level of physical activity, hypertension, smoking, and overweight were associated with a lower VO2peak. History of stroke and stroke characteristics were not related to VO2peak. Conclusion The majority of patients with a recent TIA or minor ischemic stroke have a poor CRF. Our findings suggest that premorbid cardiovascular and pulmonary disease and vascular risk factors, but not TIA- or stroke-related factors, contribute to a reduced CRF.

Water column currents and bottom temperature from September 2005 to September 2006 across the narrow shelf region off Port Edward on the east coast of South Africa, combined with satellite observations, highlighted the dominant influence of the Agulhas Current (AC) on shelf circulation. Stronger southwestward flow occurred across the shelf during austral summer and autumn suggesting an intensification and shoreward movement of the AC during these seasons. In situ moored observations also showed that the AC extended as far inshore as 3.2 km from the coast. Weak and non-significant correlations between wind and current, and between wind and bottom temperature, indicated minimal influence of local wind forcing on current variations and temperature responses. A total of 11 northeasterly flow events, ranging from 1 to 15 days, were observed, with only 4 events associated with the passage of mesoscale cyclonic eddies along the inshore edge of the AC. The remaining events all suggested small-scale movements of the AC resulting in enhanced Ekman veering in the bottom layers further offshore, and full water column current reversals close inshore. Contrary to expectation, no clear seasonal variation in bottom temperatures was evident, and temperatures and currents were poorly correlated, since both warming and cooling occurred during southwesterly and northeasterly flows. Substantial short-term fluctuations of up to 4 °C were associated with shoreward/offshore movements of the AC, and southward propagation of eddies. Advection of warmer AC waters around eddies and southward advection of waters upwelled further north served to complicate the observed temperature responses.

Mesoscale eddies in the Prince Edward Island (PEI) region of the Southern Ocean were identified and tracked using satellite altimetry over a 26-year period between 1993 and 2018. We further substantiated previous findings that eddies originating from the eddy hotspot east of the Southwest Indian Ridge have little direct effect on the PEIs, by demonstrating that over the 26-year period, only 3 cyclonic eddies from this hotspot region propagated close enough to interact with the PEI shelf. The majority of cyclonic and anticyclonic eddies that impacted the PEIs originated from the southern branch of the sub-Antarctic Front (S-SAF) and the northern branch of the Antarctic Polar Front (N-APF), further highlighting the importance of these fronts to the island ecosystem. Despite the fact that fewer than 10 eddies per year directly impact the islands, these eddies remain in contact with the PEI shelf and can thus influence conditions for a considerable part of the year, with eddy stirring likely influencing the islands more frequently than eddy trapping. There was no clear seasonal variation in the number and characteristics of these eddies, and long-term trends were also weak and mostly non-significant, likely due to the small number of eddies observed and the large variability between months and years. Nevertheless, our study presents the first 26-year investigation of the temporal variability of mesoscale eddies influencing the PEIs, providing a good baseline against which future changes can be assessed.

Mesoscale eddies are known to strongly influence oceanographic properties and biological responses. Since eddies can transport physical characteristics and biota, knowledge of their origin, pathways, and characteristics is important for understanding their potential impacts on ecosystems such as the Prince Edward Island (PEI) archipelago. Over a 26-year period (1993–2018), a total of 395 (724) cyclonic and 377 (515) anticyclonic eddies were identified and tracked using satellite altimetry in the PEI and Southwest Indian Ridge (SWIR) regions of the Southern Ocean, respectively. The majority of these eddies were formed locally, were relatively short-lived (

While it has been established that nutrients and flavours (odour, taste) play an important role in diet selection by horses, previous studies have not always clarified what type of flavouring (e.g. non-nutritive or nutritive) was used. Therefore, the objective of this study was to determine the influence of distinct food characteristics (odour, taste, nutrients) on the preference of horses using different preference testing protocols. This experiment consisted of three phases; adaptation (P1), two-choice testing (P2) and multiple-choice testing using a chequerboard design (P3). Four pelleted diets equal in digestible energy, but contrasted in crude protein (LP; 14% and HP; 27%) and added non-caloric (natural) sweetener (i.e. LP, LP+, HP, HP+) were consecutively fed to each of sixteen adult horses. The diets were paired with four non-nutritive odours (coconut, banana, cinnamon, spearmint), with a unique odour and diet combination allocated to each group of four horses. In P1, each diet was presented solely for five days to facilitate pre- and post-ingestive associations; in P2 a two-choice test was conducted with four diet combinations (contrasts) over three days; and in P3 the four diets were presented simultaneously in a checkerboard fashion over a 5-day period. Feed intake, bucket/zone visits and time spent foraging or moving were recorded. The key findings of this study were: (1) In P1 an initially large variation in intake was recorded with only some horses showing a neophobic response to a new odour/food, but variation declined within 2 days with the majority of the horses consuming over 90% of the diets. (2) Nutrient (HP) content appeared to be the main driver for diet intake in P2 (P < 0.05) and P3 (P < 0.001). (3) Taste appeared to be the secondary determinant of preference and this was more evident with the LP diet. (4) Consumption of diets linked to sweet aromatic odours (banana and coconut) was greater in P3 (P < 0.001). (5) The multiple-choice test, which was designed to promote patch foraging behaviour, showed more explicit differences in diet ranking compared to the two-choice test. These findings confirm previous studies that horses prioritise diets on nutrients, but this is the first equine study that shows the positive influence of a non-caloric natural sweetener on diet choice. A non-nutritive sweet taste or odour appears to encourage diet intake by horses, but more research is needed that examines different sweeteners coupled with and without odour and/or dietary nutrients and its long-term effects on food intake.

Summary Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.

While it has been shown that diet selection by equids can be influenced by nutritional factors, it is presently unclear how diet choices by horses are modulated when animals are faced with a familiar-novel dichotomy. Therefore, this study aimed to investigate the effect of energy intake on foraging behaviour in horses and the selection of familiar (FF) and nutritious novel (NF) forages. Twelve adult mares were maintained in yards during feeding and were housed in two groups in barren paddocks when not feeding. The experiment lasted for 8 weeks; in weeks 0, 4 and 8 horses received a maintenance diet and in weeks 1–3 and 5–7 horses were switched to a low energy (LE; 80% RDI) or high energy (HE; 120% RDI) diet. In weeks 3 and 7 a two-choice test was presented in a split-plot design, with 12 horses being the main-plot units. The LE and HE diets were applied at the main-plot level (n=6) while the subplots were the 10 min feeding intervals (combined over 3 consecutive days) where horses (one at a time) were introduced to a forage preference test (1 to 4). The tests were made up as pairs, based on the nutritional profile, with one being FF (oaten or lucerne chaff) and the other feed was NF (bamboo, tagasaste, willow or saltbush leaf chaff) and presented in a checkerboard design. In wk 8 the preference of all forages together was examined. Forage intake, the number of visits to each zone/bucket and time spent foraging or moving toward each zone/bucket were recorded. Horses demonstrated a greater preference for FF, but there were no differences between the LE and HE diet groups in the proportions of intake of NF. There was a higher acceptance of NF on Day 1, which declined on Day 2 and 3 for both diet groups (P

The Agulhas Current is a major Western Boundary Current that flows along the southeast slope of southern Africa and has an influence on the biogeochemistry of adjacent ecosystems through localised upwelling of cool, nutrient-rich water up the slope and onto the shelf. Variability in pigments and absorption were therefore examined to determine the adaptation of phytoplankton communities to changing nutrient and irradiance conditions during mid-summer. Chlorophyll a concentrations varied from 0.1 mg m−3 offshore to 7.3 mg m−3 inshore in response to the nutrient enrichment. CHEMTAX analysis revealed that diatoms were the dominant group at most of the inshore stations, mixed populations of diatoms, haptophytes and prasinophytes characterised the shelf edge populations, while haptophytes and Prochlorococcus dominated the offshore stations over the slope. Diatom populations were associated with cool, lower salinity water and prokaryotes with warm, higher salinity water, while flagellates occurred in both water types. Nutrient relationships deviated from Redfield ratios and there appeared to be a greater uptake of silicate at elevated nutrient levels where diatoms were dominant, but nitrate was preferably utilized at low concentrations when flagellates and prokaryotes comprised the communities. Populations acclimated to changing irradiance by adjustments in their absorption and proportion of accessory pigments. Prokaryote dominated communities had high chlorophyll-specific absorption coefficients and a high proportion of chlorophyll a and photoprotective carotenoids. Diatoms had low chlorophyll-specific absorption and elevated proportions of photosynthetic carotenoids and chlorophyll a. Flagellate dominated communities had intermediate chlorophyll-specific absorption and had elevated absorption by chlorophyll a, chlorophyll b and photosynthetic carotenoids. Ratios of UV absorption at 330 nm to chlorophyll a absorption at 676 nm displayed an increasing trend with increased irradiance near the surface, particularly for prokaryotes. Overall, nutrients and irradiance were the main drivers influencing phytoplankton adaptation and acclimation.

Background The CAPICE project aims to 1) identify genetic variants associated with the occurrence and course of common childhood psychopathology including depression, anxiety and Attention Deficit Hyperactivity Disorder related traits, and establish the genetic overlap within childhood psychiatric disorders and with adult psychiatric disorders, 2) unravel the mechanisms underlying the associations between early lifestyle factors and childhood psychiatric disorders, 3) identify new drug targets, and 4) build a risk prediction model that identifies groups of children that are at highest risk to have persistent symptoms. This poster provides an overview of the plan to achieve these goals. Methods CAPICE is an international training network, funded by an EU Marie Curie grant, in which 12 PhD students will be trained in psychiatric genomics. This network will elaborate on the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. EAGLE is a well-established collaboration of many birth and adolescent population based (twin and family) cohorts, with unique longitudinal information on lifestyle, family environment, health, and emotional and behavioral problems. Phenotypic and genome-wide data are available for over 60,000 children, in addition to genome-wide data for over 20,000 mothers and epigenome-wide data for over 6,000 children. Analyses will include (but will not be limited to) twin analyses, genome-wide association meta-analyses, polygenic analyses, Mendelian randomization, and biological pathway analyses. Results We expect that the results will provide insight into the etiology of mental health symptoms in children and adolescents and shed light on possible targets for prevention and intervention (e.g. by drug target validation or by tailoring treatment based on the risk for persisting symptoms). Discussion It is well known that psychiatric symptoms in childhood be the precursor of many psychiatric disorders during adulthood. Longitudinal population based cohorts provide a good opportunity to show how genetic factors influence development over the ages. Since these disorders are the extreme end of the continuum, collaborations with case-control samples may strengthen the results.

Variability of hydrographic characteristics and phytoplankton distribution associated with mesoscale eddies in the Mozambique Channel was investigated during four cruises in September 2007, December 2008, November 2009, and April/May 2010. Satellite altimetry was used to map the location of mesoscale features, and together with ETOPO1 bathymetry, was used in a Discriminant Function Analysis to classify in situ sampling stations into five categories, namely cyclonic (C), anti-cyclonic (A), frontal (F), divergence (D), and shelf (S). Fluorescence profiles were integrated through four depth ranges in the upper 200 m and used to determine the depth of the maximum chlorophyll a concentration and to model the euphotic zone depth. At a depth of 100 m, distinctly different hydrographic characteristics were observed between mesoscale features with cyclonic eddies consisting of Subtropical Surface Water and anti-cyclonic eddies containing Tropical Surface Water from the Indian Ocean. Hydrographic properties at divergence and frontal stations reflected a mixture of these water masses, while shelf stations showed considerable variability as a result of the interaction of eddies with the continental slope. Chlorophyll a concentrations in the surface waters were found to be low, with subsurface levels being significantly greater. Phytoplankton biomass in cyclonic and anti-cyclonic eddies was relatively low and not significantly different. The interaction of mesoscale eddies with the continental slope on the western side of the Channel caused upwelling of cooler, nutrient-rich water, which resulted in elevated phytoplankton biomass in the shelf regions. Strong currents at the perimeters of these eddies produced offshore advection of the high biomass into the frontal regions.

An investigation of phytoplankton pigment and absorption characteristics was undertaken during three research cruises in the Mozambique Channel to elucidate community structure and examine the adaptation of populations to mesoscale features at the surface and the deep chlorophyll maximum (DCM). Total chlorophyll a concentration (TChla) at the surface was determined to be greater in cyclonic eddies than in anticyclones, while TChla in divergence and shelf zones were similar to cyclones, with frontal zones being slightly lower. TChla at the DCM was similar for all categories, although there was a tendency for anticyclones to have lower TChla. Prokaryotes were the most significant phytoplankton group at the surface, with small flagellates also being of secondary importance, while flagellates dominated at the DCM. A few shelf stations, and frontal and shelf stations close to the shelf, displayed high TChla and diatom domination, particularly at the DCM. Absorption properties and photopigment indices revealed that prokaryote dominated communities had high chlorophyll-specific absorption coefficients, a large range in the proportion of TChla within the total pigment pool and a high proportion of photoprotective carotenoids. Diatoms had low chlorophyll-specific absorption, a relatively high proportion of TChla, and elevated proportions of photosynthetic carotenoids and chlorophyll c. Flagellate dominated communities had intermediate chlorophyll-specific absorption, a lower proportion of TChla, elevated photosynthetic carotenoids and intermediate chlorophyll c.

Introduction/Background The need for rehabilitation is growing although there are limited resources to meet this demand. Use of affordable technologies to enable health professionals to prescribe and monitor rehabilitation remotely may be one strategy to meet this demand. Aim: to describe physiotherapy support provided to participants using technology to improve mobility and physical activity in the post-hospital phase of the AMOUNT rehabilitation trial (n = 300). Material and method Process evaluation including participants (mean age 70 (SD 18); 52% male; 54% with neurological conditions limiting mobility) randomised to the intervention group (n = 149). Intervention was additional to standard rehabilitation, prescribed using a protocol which matched games/exercises from eight technologies to the participant's mobility limitations. Technologies included video and computer games/exercises, tablet applications and activity monitors. Participants were taught to use the technologies during inpatient rehabilitation and were then discharged home to use the technologies ≥ 5 days a week for the remainder of the 6-month trial. Trial protocol required the physiotherapist to provide support every 1–2 weeks using a health coaching approach. Intervention datasheets were audited to determine frequency, duration, mode and type of support provided. Results Participants used on average 2 (SD 1) technologies in the post-hospital phase, with 95% of participants using an activity monitor. Physiotherapists had contact with participants on average 15 (SD 5) times (approximately every 11 days), of which eight were phone calls (11 min duration), six home-visits (46 min duration) and one other. Contact primarily incorporated health coaching (68%) with 8% of contact specifically for technology support. Topics discussed during health coaching included discussing data from prescribed technologies (79%), physical activity and mobility status (70%), adherence (64%) and goal setting (47%). Conclusion A health coaching model to support technology-based rehabilitation post-hospitalisation is feasible. Some support can be provided remotely limiting the need for frequent home visits.

Introduction/Background New technologies may provide an affordable way to increase the dose of practice for people undertaking rehabilitation. Study aims: (1) Which technologies were used to address participants’ mobility limitations during the inpatient phase of the AMOUNT rehabilitation trial? (2) Did participants perceive technologies to be enjoyable and easy to use, and which factors influenced this? Material and method Design: process evaluation from a randomised controlled trial in which 149 participants [52% male; mean age 70 (SD18); 54% neurological conditions] were allocated to the intervention group. Intervention: tailored technology prescription according to a protocol matching exercises from eight technologies (commercially-available: Nintendo Wii; Xbox Kinect; activity monitors; smartphone apps; rehabilitation-specific Humac; Fysiogaming; Stepping Tiles; exercise iPad apps) to seven mobility limitations. Outcome measures: intervention dose, technologies used, mobility limitations addressed, Physical Activity Enjoyment (PACES; 18–126) and System Usability Scales (SUS; 0–100). Results Participants received on average 11 (SD11) sessions of 43 (SD11) minutes duration. Each participant used on average 4 (SD1) technologies to address a mean of 4 (SD1) different mobility limitations. Intervention focused largely on limitations related to standing (80%) and stepping (79%), as well as on physical activity levels (90%). The Humac was the most frequent first-introduced technology (35% of participants). Activity monitors (80%) and iPad apps (71%) were most prescribed, and commercially-available exergames and smartphone apps used least. At 3 weeks, participants perceived technology use as enjoyable [mean PACES 95.4 (SD23.2)] and rated usability above average [mean SUS 72.2 (SD18.8)]. Enjoyment and usability were positively related to previous technology use (P Conclusion In inpatient rehabilitation, tailored prescription of technologies can address a range of mobility limitations and was well accepted. Previous technology use enhances uptake.

The Agulhas Current, the largest Western Boundary Current in the Southern Hemisphere, strongly influences the oceanographic conditions of its adjacent shelf system. As a result of limited societal drivers, such as large-scale fisheries and marine mining, the South African southeast shelf, between Port Elizabeth and Port Shepstone, is one of the least studied and under-sampled shelf systems in Southern Africa. This study describes hydrographic conditions from the first two shelf-wide high-resolution surveys (January/February and July/August 2017) of this region. These data provide a baseline of environmental conditions and hydrographic processes across the shelf. The Agulhas Current, as well as cyclonic mesoscale eddies along the inshore edge of the Current, were observed to strongly drive conditions on the shelf. Substantial differences in the impacts of these cyclonic eddies were evident, with the smaller less intense January/February eddy inducing much stronger upwelling than the larger more intense July/August eddy. Indications of seasonality in temperature, salinity and chlorophyll-a were observed in the surface layers. Surface waters were 4 °C warmer in January/February than in July/August. Considerably lower salinities (33.77 g kg−1) were observed in January/February as a result of high rainfall and subsequent increased river outflow. Upwelling mechanisms such as divergence-induced upwelling, Ekman veering in the bottom boundary layer, Ekman pumping associated with cyclonic eddies, were observed to uplift colder, nutrient-rich water from deeper layers onto the mesotrophic shelf. These colder waters ultimately reached the surface as a result of wind-driven Ekman transport and vertical mixing. Tropical Surface Water, Subtropical Surface Water and South Indian Central Water were observed on the shelf. Red Sea Water as well as Antarctic Intermediate Water generally occupied the slope regions except where cyclonic eddies uplifted intermediate waters onto the shelf. The shelf-wide dissolved oxygen levels (>3 ml l−1) suggested that oxygen availability adequately facilitated the survival of the existing shelf biology.

Data from the Pierre Auger Observatory are analyzed to search for anisotropies near the direction of the Galactic Centre at EeV energies. The exposure of the surface array in this part of the sky is already significantly larger than that of the fore-runner experiments. Our results do not support previous findings of localized excesses in the AGASA and SUGAR data. We set an upper bound on a point-like flux of cosmic rays arriving from the Galactic Centre which excludes several scenarios predicting sources of EeV neutrons from Sagittarius $A$. Also the events detected simultaneously by the surface and fluorescence detectors (the `hybrid' data set), which have better pointing accuracy but are less numerous than those of the surface array alone, do not show any significant localized excess from this direction., Comment: Matches published version

The use of traffic control systems can potentially improve the traffic flows on traffic networks. However, for the implementation of such control systems—both in simulation and in practice—many steps should be taken, and many choices are to be made. In this paper a list of considerations is provided for developing model-based traffic control systems in general, with a more detailed discussion on the use of model-predictive control for traffic regulation. A case study of designing a traffic controller is provided for the Dutch A12 freeway.

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses peanut sensitization by affecting T cell subsets. However, effects of AhR activation on dendritic cells (DC) in an allergic setting were not investigated yet. Therefore, we analysed the effects of AhR activation on DC phenotype in vivo, as well as their ex vivo potency to stimulate allergen-specific splenic T cells and to induce CD4+CD25+Foxp3+ regulatory (T(reg)) cells. C3H/HeOuJ mice were treated with TCDD by gavage and subsequently sensitized to peanut extract (PE). After eight days, mice were sacrificed and DC in spleen and mesenteric lymph nodes (MLN) were characterized or cocultured with PE-specific CD4+ T cells. AhR activation almost doubled the absolute number of CD11c+CD103+ DC, while not affecting CD11b+ DC, the absolute number of DC, the expression of the activation makers MHCII, CD86, CD80, CD40, CD54 and CD8 on CD11c+ and the activation status of CD11c+CD103+ DC in the spleen. In the MLN, TCDD decreased the absolute number of DC and CD103+ DC, while not affecting CD11b+ DC and the expression of activation markers on DC. PE-pulsed splenic DC from TCDD-treated mice suppressed IL-5, IL-13 and IFN-γ production by PE-specific T cells, but did not induce CD4+CD25+Foxp3+ T(reg) cells. This suppression of cytokine production was not mediated by the TCDD-induced increase in CD103+ DC in the spleen. Combined, these results indicate that AhR activation suppresses the initiation of food allergic responses by affecting DC and their interaction with effector T cells.

Contains fulltext : 118802.pdf (Publisher’s version ) (Closed access) OBJECTIVE: In endometrial carcinoma, myometrial invasion is a well known predictor of recurrence, and important in the decision making for adjuvant treatment. According to the FIGO staging system, myometrial invasion is expressed as invasion of of the myometrium (50%MI). It has been suggested to use the absolute depth of invasion (DOI), or the tumor free distance to the serosa (TFD). The aim of this study was to compare DOI, 50%MI, and TFD. METHODS: All patients diagnosed with endometrioid endometrial carcinoma at the RUNMC, and the CWH from 1999 to 2009 were included. Histologic slides were reviewed for histologic type and grade, DOI, 50%MI, and TFD. After review, 335 patients were identified. DOI, 50%MI, and TFD were evaluated for their prediction of clinicopathologic characteristics. RESULTS: The prediction of recurrence was best performed by DOI when compared to TFD, with an area under the ROC curve of 0.726, and 0.638 respectively. The optimal cut-off value for DOI was 4mm. DOI independently correlated with recurrence of disease, and death of disease. TFD was associated with advanced age and large tumor diameter. DOI was the best predictor of progression-free and disease-specific survival next to 50%MI and TFD (HR 3.15, 95%CI 1.16-8.56) and (HR 10.35, 95%CI 1.23-86.93). CONCLUSIONS: DOI showed better predictive performance than TFD, and was more strongly correlated with clinicopathologic parameters than TFD and 50%MI. Possibly, DOI should substitute 50%MI as measure to express myometrial invasion in daily clinical practice. External validation is mandatory to confirm the proposed cut-off value of 4mm.

Future planning has previously been considered unique to humans. However, certain animals can foresee some of their future needs. We tested long-tailed macaques (Macaca fascicularis) ability to transport and after a delay use a rake, in two experiments. Firstly, six rake tool-trained macaques failed to select and after a delay, transport the rake. Secondly, five of the macaques were shaped on transporting the rake for immediate rewards. Now, all of the macaques transported and used the rake after a delay of 5 min; one was successful after 10 min and even on a few trials after 20 min. The macaques failed to plan in the first experiment, potentially because they were unable to foresee the appropriate sequence of behaviours to solve the task. After shaping, they displayed flexibility by successfully transporting tools after delays. Remarkably, several macaques generalized this behaviour by attempting to use non-provided objects or their tails. Our results show which information and experience macaques need in order to display tool transport for future use.

For the computational solution of the acoustic scattering problem, new domain integral equations are proposed. These domain integral equations describe the acoustic wave propagation in some chosen inhomogeneous background, whereas the influence of the scattering object is viewed as a superposition of contrast sources. A stretching procedure of the inhomogeneous background to a homogeneous one leads to a domain integral equation in a stretched space, where the Green function has the same simple functionality as the one of the non-stretched homogeneous background. This leads to improved efficiency in the computation of the scattering problem at hand.

Drugs of abuse are known to mainly affect the dopaminergic and serotonergic system, although behavioral studies indicated that the GABA-ergic system also plays a role. We therefore investigated the acute effects of several commonly used drugs of abuse (methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α(1)β(2)γ(2) GABA(A) receptor (hGABA(A)-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Although none of the tested drugs acted as full agonist on the hGABA(A)-R, some drugs induced differential modulation of hGABA(A)-R function, depending on the degree of receptor occupancy. Methamphetamine did not affect the GABA-evoked current at high receptor occupancy, but induced a minor inhibition at low receptor occupancy. Its metabolite amphetamine slightly potentiated the GABA-evoked current. MDMA and its metabolite MDA both inhibited the current at low receptor occupancy. However, MDMA did not affect the current at high occupancy, whereas MDA induced a potentiation. mCPP induced a strong inhibition (max. ∼ 80%) at low receptor occupancy, but ∼ 25% potentiation at high receptor occupancy. Competitive binding to one of the GABA-binding sites could explain the drug-induced inhibitions observed at low receptor occupancy, whereas an additional interaction with a positive allosteric binding site may play a role in the observed potentiations at high receptor occupancy. This is the first study to identify direct modulation of hGABA(A)-Rs as a novel mode of action for several drugs of abuse. Consequently, hGABA(A)-Rs should be considered as target for psychiatric pharmaceuticals and in developing treatment for drug intoxications.

In breast cancer, the interaction between estrogen-producing breast adipose fibroblasts (BAFs) and estrogen-dependent epithelial tumor cells is pivotal. Local estrogen production is catalyzed by aromatase, which is differentially regulated in disease-free and tumorigenic breast tissue. The use of aromatase inhibitors to block local estrogen production has proven effective in treatment of estrogen-dependent breast cancer. However, a major problem during breast cancer treatment is the sudden onset of menopause and many women seek for alternative medicines, such as the soy isoflavone genistein. In this study, we show that genistein can induce estrogen-dependent MCF-7 tumor cell growth and increase breast cancer-associated aromatase expression and activity in vitro. We have previously developed an in vitro breast cancer model where the positive feedback loop between primary BAFs and estrogen-dependent MCF-7 tumor cells is operational, thereby representing a more natural in vitro model for breast cancer. In this model, genistein could negate the growth inhibitory action of the aromatase inhibitor fadrozole at physiologically relevant concentrations. These data suggest that soy-based supplements might affect the efficacy of breast cancer treatment with aromatase inhibitors. Considering the high number of breast cancer patients using soy supplements to treat menopausal symptoms, the increasing risk for adverse interactions with breast cancer treatment is of major concern and should be considered with care.

We show in the smooth category that the heat trace asymptotics and the heat content asymptotics can be made to grow arbitrarily rapidly. In the real analytic context, however, this is not true and we establish universal bounds on their growth.

The fast and non-destructive character of neutron radiography provides the possibility of in-situ investigations of hydrogen uptake and diffusion in zirconium alloys. A special reaction furnace with neutron transparent windows was constructed. The method of quantitative hydrogen determination by neutron transmission measurements was calibrated for each experimental run. Additionally, oxygen is absorbed in the α-Zr phase and precipitated in the oxide layer. The calibration of the correlation between hydrogen and oxygen concentrations and total neutron cross-sections at room temperature and between 1123 and 1623 K are described. Results of in-situ neutron radiography investigations of hydrogen diffusion and absorption are presented in this paper. A linear dependence of the total macroscopic neutron cross section on the H/Zr atomic ratio as well as on the oxygen concentration was found. No significant temperature dependence of the total neutron cross-sections of hydrogen dissolved in β-Zr or oxygen dissolved in the α-Zr or precipitated in the oxide layer was found.

Methylation-mediated silencing of the tumour suppressor CADM1 has been functionally linked to lung cancer development. We aimed to determine whether CADM1 promoter methylation is a candidate early detection marker for lung cancer. To this end frozen tissue samples of 36 non-small cell lung cancers, 26 corresponding tumour distant normal tissue samples as well as 6 samples of normal lung from non-lung cancer patients were tested for DNA methylation at three different regions within the CADM1 promoter (M1, M5 and M9) using methylation specific PCR followed by methylation specific reverse line blot analysis.Sixty-four percentage of tumour samples tested positive at the M1 region, 47% at M5 and 74% at the M9 region, compared with 65% (M1), 23% (M5) and 46% (M9) of paired normal tissue samples. Methylation of each of these promoter regions was also detected in the majority of non-lung cancer control samples. Dense methylation, defined as methylation at ≥2 promoter regions, was detected in 66% of tumour samples compared with 38% of paired normal tissues and 67% of non-lung cancer control samples. Within the small subgroup of female patients dense methylation was found in all tumour samples but only 22% of paired normal samples. Neither methylation of individual sites nor dense methylation was correlated with disease free survival. In conclusion, CADM1 promoter methylation is a frequent event in NSCLC as well as normal lung, both of lung cancer and non-lung cancer patients. Hence, CADM1 methylation analysis is unlikely to have diagnostic value for the early detection of lung cancer in an unselected population. However, a diagnostic value for selected subjects, such as females, cannot be excluded.

Background and Study Aims: Screening programs for lung cancer may lead to a heightened awareness of the risks of smoking and enhance quitting. The aim of this study was to evaluate whether the participation on a chemoprevention study for premalignant lesions could influence smoking cessation. Methods: Two hundred one volunteers, current (n 188) and former smokers (n 13) with more than 20 pack years had been screened for the chemoprevention study. One hundred forty-six of the current smokers at time of chemoprevention study screening have been retrospectively interviewed about their smoking behavior 1 year after their first contact for the chemoprevention study. Structured questionnaires were used, and interviews were held by telephone. The quitters at the time of these first interviews were contacted again 4 years after the initial interview about their current smoking behavior. Results: Of the 146 smoking volunteers, 83 were diagnosed with premalignant lesions of the bronchial mucosa and participated in the chemoprevention study, and 63 had no premalignant lesions and were not included in that study. The majority of participants were men: 87 (60%). The mean age of the participants was 52 9 years, and the mean age at which volunteers started smoking was 15 3. Mean number of pack years was 47 27. Ten volunteers in the group without premalignant lesions and 19 in the group with premalignant lesions had quit smoking at time of the first interview. The smoking cessation rate of the total study group was 20%. Univariate logistic regression analysis demonstrated that smoking cessation was only significantly associated with male gender. No significant associations were found between smoking cessation and the finding of premalignant lesions, sex, age, level of addiction, educational level, marital condition, history of cancer/ pulmonary diseases, age at start smoking, previous attempts to quit smoking, and motivation to quit smoking. Within the group of subjects who had quit smoking at the time of the first interview, 15 of 29 persons who had stopped smoking at the time of the first interview have reported that participation in the bronchoscopy screening and/or the trial has been of major influence on their decision to stop smoking. Conclusions: A smoking cessation rate of 20% has been found among volunteers for a chemopreventive trial investigating smoking-related premalignant lesions after almost 2 years after initial contact has been found. Volunteers experienced screening and trial participation as having influenced their smoking cessation. Smoking cessation was significantly associated with male gender, whereas the finding of premalignant lesions by bronchoscopy was not.

Introduction/Background An avatar-directed scheduling and memory aid app (Anna Cares™) was identified as a potential solution to scheduling difficulties in busy rehabilitation services. However, there are well-documented difficulties with clinician acceptance and uptake of technology. This study investigated clinician perspectives of Anna Cares for use within two rehabilitation teams. Material and method Two focus groups were conducted with sixteen clinicians from various disciplines working in two rehabilitation settings at a metropolitan hospital in Adelaide (SA, Australia). Focus groups aimed to explore, clinicians’ perceptions of acceptability and usefulness of the app, and their attitudes towards this type of technology in general. Clinicians also completed self-assessed technology proficiency, perceived usefulness, and perceived ease of use scales. Results Clinicians described time constraints and the reliable scheduling of therapy sessions to be of significant importance, and they welcomed technology that could assist with this. They liked the concept of the avatar and found the app novel and fun. However, the preparation of the app for use with patients was problematic and time consuming. The more experienced clinicians found the app more difficult to use (r = .586, P = .027) and did not see the app as beneficial to their patients nor did the technology add value to delivery of care. There was a significant relationship between age and mean value for ease of use (r = .540, P = .046) but no significant relationship between age or experience, and the mean score for usefulness. Nor did there appear to be a relationship between self-assessed level of technology proficiency and either perceived usefulness and perceived ease of use. Conclusion Although clinicians appreciated the concept of an avatar-directed scheduling and memory aid, they did not see it as a useful tool in the provision of scheduling assistance in short-term rehabilitation services.

Introduction/Background The development of services that provide home-based rehabilitation for stroke patients has attracted increasing interest. Research has demonstrated this new rehabilitation approach should include a psychosocial component. The purpose of this study was to evaluate the use, feasibility and acceptability of virtual assistant technology to provide post-discharge psychosocial support for people with stroke receiving telerehabilitation, and their caregivers. Material and method This was a pragmatic usability study using a convenience sample from a hospital based home rehabilitation service. For four weeks Anna acted as a virtual assistant via a tablet application, and provided participants with 11 different health coaching sessions (HCS) delivering stroke-specific educational content. Other app features included daily facts, scheduling and messaging. Outcome measures were app usage, ease of use and usefulness (7-point Likert scale). Additional in-depth interviews explored participants’ perspectives on the assistive mobile technology. Results Fifteen patients (71% male, mean age 67 ± 11 years) and their caregivers followed the program. Adherence was high, with on average 8.4 ± 2.9/11 HCS completed. The use of calendar and messenger functions ranged from never to frequent. Ease of use (mean 6.1 ± 0.9) and usefulness (mean 6.2 ± 1.3) scores were high. In the interviews, participants considered the HCS informative, relevant and comprehensive. The majority of patients evaluated Anna as supportive and encouraging. All expressed preference for an avatar based app over other ways of information provision and all believed Anna supported them in their rehabilitation program. Conclusion The participants related to, and felt supported by the virtual health coach Anna. Virtual assistant technology seems a feasible and acceptable means of providing educational information, HCS, and support among community-dwelling people with stroke and their caregivers. Future studies are required to determine the potential benefit of this support system on health outcomes as well as costs.

Water stress affects the rate of water uptake, biomass accumulation and structural growth of sugarcane differently and, consequently, alters the partitioning of assimilate to sucrose storage. The CANEGRO sugarcane model is unable to accurately simulate the subtle rate changes in the source and sink processes during the progression of water stress during dry spells, with subsequent poor prediction of sucrose yields. The aim of this study was to test eight different water balance models by comparing simulated and experimentally determined rates of water uptake (WU), carbon assimilation (CAR), plant extension (PER) and sucrose accumulation (SA). Data from two experiments conducted in a rainshelter at Mount Edgecombe, South Africa were used: in the 2002/03 trial, WU, CAR, PER, SA were monitored over a 40-day period starting with 5-month-old well-watered sugarcane, which then received either adequate or no water (Experiment A). The 1998/99 trial was conducted under similar conditions, but with the stress treatment imposed at 3 months after planting (Experiment B). The approaches to modelling WU evaluated ranged from a simple approach based primarily on whole profile soil water content to relatively complex approaches taking account of layer specific soil water retention and root density. Results show that the fraction of available soil water at which soil water supply started limiting WU varied from 0.129 in Experiment A to 0.307 in Experiment B. The difference is ascribed to a difference in evaporative demand at that time. PER (sink activity) responded to water stress much sooner (14 days) and at much higher fractional soil water contents (0.81 compared with 0.14 in Experiment A) than CAR (source activity). SA was enhanced marginally in Experiment A and markedly in Experiment B due to mild water stress, presumably due to the differential impacts of water stress on source and sink activity. Severe water stress led to a cessation of sucrose accumulation. Increased modelling complexity did not necessarily result in better predictions of WU for these experiments. All models except CANESIM predicted the onset of reduced WU uptake to within 3 days of estimated actual onset. Simple models simulated a more gradual decline in WU with increasing stress levels than complex models, and mimicked actual decline closer. BEWAB was chosen as the most appropriate WU model for inclusion in CANEGRO because of its more gradual extraction of water as stress progresses. All models simulated smaller time differences between the onset of reduced sink activity and source activity than was observed. The best WU models in this respect were BEWAB and CANESIM. Using the BEWAB WU model also resulted in better simulations of CAR and PER. However, all models, except the CANESIM model, underestimated the early impact of water stress on PER. All models performed surprisingly well to simulate subtle changes in SA due to mild water stress. The BEWAB WU model with an adjusted water stress impact equation produced the best predictions of SA. It is recommended that the appropriate changes be made to the CANEGRO model and then to thoroughly re-validate yield predictions for many different cropping situations.

Clinical prediction models for factor VIII inhibitor development may potentially facilitate the identification of patients at high risk of this complication. In particular, recognition of early intensive FVIII replacement therapy as a significant risk factor for inhibitor development has defined a clear clinical decision point that influences patient care. To assess the effect and potential acceptance of a prediction tool for FVIII inhibitor development in clinical practice, a 15-item survey was developed to assess whether these included items were accepted as potential risk factors by the health care providers taking care of these patients. The rating of these items was on a 5-point linear scale, with '1' representing it to be very unlikely and '5' very likely. Responses from 42 centers were available for analysis. These centers were responsible for taking care of 2642 children18 years with severe hemophilia A. In addition to genetic factors (mean score approximately 4.5), early intensive treatment was considered important for inhibitor development (mean score 4.07). Other factors likely to reduce inhibitor development were early onset of prophylaxis (mean score 3.68) and avoidance of early surgery (mean score 4.05). Physicians also agreed that institution of early prophylaxis and avoidance of elective surgery are important management strategies to reduce inhibitor development (mean scores 3.54 and 4.32, respectively).

Policy objectives of attaining food self-sufficiency and improving the well-being of subsistence farmers while protecting the environment have stimulated the development of many improved agricultural production technologies. With a choice of technologies, farm household decisions are governed not only by productivity and profitability considerations but also by factors such as available resources and their quality, family consumption preferences and attitudes towards risks, and prevailing policies. It is therefore necessary to analyse the adoption of such technologies from a whole-farm perspective. In this paper, a farm household model is used to assess possible technology adoption behaviour of farmers in Ilocos Norte Province, Philippines. Four alternative technologies were evaluated: hybrid rice production (HYR), balanced fertilization strategy (BFS), site-specific nutrient management (SSNM) and integrated pest management (IPM). Possible impacts of price policies and infrastructure improvements on technology adoption were assessed. The results show that all four alternative technologies considered are attractive to farmers, although simulations show differential adoption rates for poor, average and better-off households. IPM and HYR appear the most attractive amongst all technologies considered. In all technology simulations, relative profitability and risks, labour and capital requirements and availabilities are decisive factors in the adoption of alternative technologies. Adoption of alternative technologies would result in higher discretionary income, higher rice production and lower biocide use and nitrogen loss. Amongst policy simulations considered, availability of low-cost credit shows the largest improvements in farmer welfare for poor and average households, but its effect on simulated adoption of alternative technologies was variable. We argue that the methodology and results presented can contribute to ex ante assessments of policies targeted at stimulating technology adoption by farmers.

In this paper we introduce a Conjugate Gradient Fast Fourier Transform (CG-FFT) scheme for the numerical solution of the integral equation formulating three-dimensional elastic scattering problems. The formulation is in terms of the stress tensor and particle velocities as the unknown field variables. In contrast with the formulation based on particle displacements, this approach leads to integral representations that do not involve derivatives of the unknown fields, thus resulting in simplified and more stable numerics. The numerical procedure is based on suitable quadrature formulas that provide (second order) accurate approximations while retaining the convolution nature of the relevant integrals that make them amenable to efficient evaluation via FFTs. The scheme is further improved through the introduction of (approximation-based) pre-conditioners that are shown to accelerate the convergence of the CG iterations. Numerical results are presented that demonstrate the accuracy and efficiency of the proposed methodology.

This article focuses on the use of online interactive peer feedback in higher education and identifies the successful uptake of feedback as an important aspect. We investigate the link between the nature of students’ feedback, the way it is evaluated by the receiver, and its consecutive use for the revision of students’ products. Two separate studies were conducted to investigate the link between these three variables across different educational contexts and tools. Both studies showed a significant relationship between feedback containing concrete suggestions and a successful uptake of the feedback. Regarding the different tools that were used, these concrete suggestions were more often produced in the Annotation system than in the Blackboard discussion forum, the latter showing more evaluative forms of feedback. We also found significant relationships between elements of both the nature and the reception of feedback on the one hand, and the use of this feedback by the receiver on the other hand.

Summary. Background: Replacement therapy in severe hemophilia A patients is complicated by formation of inhibitory antibodies against factor VIII (inhibitors) in around 25% of children. Management of bleeds and eradicating inhibitors is complicated, costly and not always successful. Objective: To develop a simple score that stratifies untreated patients with severe hemophilia according to their risk of developing inhibitory antibodies. Methods: The study population consisted of 332 children, with severe hemophilia A, selected from a retrospective multicentre cohort (the CANAL study). The score was based on risk factors available at the first treatment episode. The score was validated in an external population. Results: A total of 87 patients (25%) developed inhibitory antibodies. The selected risk score comprised positive family history (two points), high risk factor VIII gene mutations (two points), and intensive treatment at initial treatment (three points). Inhibitor incidence was 6% (six of 95) in patients without risk factor, 23% (38 of 170) in those with two points, and 57% (38 of 67) in patients with three points or more. The discriminative ability of the score was good (area under the receiver operating curve 0.74). The score performed equally well in the external validation population. Conclusion: These findings suggest that the development of inhibitory antibodies in untreated patients with severe hemophilia A can validly be predicted with the presented risk stratification score.

An investigation of pigments, phytoplankton types and absorption characteristics was conducted in the Delagoa and Natal Bights during late winter and spring in the southwest Indian Ocean. The study demonstrated that small flagellates dominated the phytoplankton communities in both bights and were ubiquitous across a temperature range of 18–24 °C. Diatoms were dominant in patches of cool water ( 22 °C. Absorption coefficients varied closely with variations in chlorophyll a and specific coefficients were lower for diatoms compared to flagellates. Chlorophyll-specific coefficients also provided useful information on the level of pigment packaging and were related to the proportion of chlorophylls and carotenoids in the pigment pool.

Although some toxicological mechanisms of sulfur mustard (HD) have been uncovered, new knowledge will allow for advanced insight in the pathways that lead towards epidermal–dermal separation in skin. In the present investigation, we aimed to survey events that occur at the protein level in human epidermal keratinocytes (HEK) during 24 h after exposure to HD. By using radiolabeled 14C-HD, it was found that proteins in cultured HEK are significant targets for alkylation by HD. HD-adducted proteins were visualized by two-dimensional gel electrophoresis and analyzed by mass spectrometry. Several type I and II cytokeratins, actin, stratifin (14-3-3σ) and galectin-7 were identified. These proteins are involved in the maintenance of the cellular cytoskeleton. Their alkylation may cause changes in the cellular architecture and, in direct line with that, be determinative for the onset of vesication. Furthermore, differential proteomic analysis was applied to search for novel features of the cellular response to HD. Partial breakdown of type I cytokeratins K14, K16 and K17 as well as the emergence of new charge variants of the proteins heat shock protein 27 and ribosomal protein P0 were observed. Studies with caspase inhibitors showed that caspase-6 is probably responsible for the breakdown of type I cytokeratins in HEK. The significance of the results is discussed in terms of toxicological relevance and possible clues for therapeutic intervention.

We study the heat content asymptotics with either Dirichlet or Robin boundary conditions where the initial temperature exhibits radial blowup near the boundary. We show that there is a complete small-time asymptotic expansion and give explicit geometrical formulas for the first few terms in the expansion.

Summary Objective A four-fold increase in the incidence of Serratia marcescens occurred in a cardio-thoracic ICU within a 13-month period. Clinical, epidemiological and molecular characteristics were analysed to elucidate the outbreak's origin. Methods Epidemiological data were analysed by mapping clustered cases; isolates were genotyped by AFLP analysis. A case–control study was performed to identify risk factors for the acquisition of S. marcescens . Data were obtained from files and electronic databases of the ICU and Department of Medical Microbiology. The adherence to hygiene protocols on the ICU was reviewed by a medical audit. Results Genotyping showed 16 distinct S. marcescens strains. Twenty-one cases and 39 controls were enrolled in the case–control study. Significant differences found by univariate analysis included the duration of surgery, APACHE-II-score on ICU admission, length of ICU stay, duration of mechanical ventilation, tube feeding and the sum of the number of days per invasive device. In a multivariate logistic regression model, the length of ICU stay and tube feeding were independent risk factors. Outbreak strains were not more frequently resistant to gentamicin, ciprofloxacin, meropenem or trimethoprim–sulfamethoxazole as compared to a reference group. Hygiene protocols, including hand washing, were insufficiently practiced by the ICU's medical staff. Conclusions The heterogeneity of the strains points to transmission from various sources. This outbreak of S. marcescens was most probably caused by reduced hand washing and other breaks in infection prevention protocols in combination with the presence of the identified risk factors, which act by affecting the number and intensity of potential transmission events.

A study was performed on two horse farms to evaluate the use of age-clustered pooled faecal samples for monitoring worm control in horses. In total 109 horses, 57 on farm A and 52 on farm B, were monitored at weekly intervals between 6 and 14 weeks after ivermectin treatment. This was performed through pooled faecal samples of pools of up to 10 horses of the groups 'yearlings' (both farms), '2-year-old' (two pools in farm A), '3-year-old' (farm A) and adult horses (four pools on farm A and five pools on farm B), which were compared with the mean individual faecal egg counts of the same pools. A very high correlation between the faecal egg counts in pooled samples and the mean faecal egg counts was seen and also between the faecal egg counts in pooled samples and larval counts from pooled faecal larval cultures. Faecal egg counts increased more rapidly in yearlings and 2-year-old horses than in older horses. This implied that in these groups of young animals faecal egg counts of more than 200 EPG were reached at or just after the egg reappearance period (ERP) of 8 weeks that is usually indicated for ivermectin. This probably means that, certainly under intensive conditions, repeated treatment at this ERP is warranted in these young animals, with or without monitoring through faecal examination. A different situation is seen in adult animals. Based on the mean faecal egg counts on both farms and on the results of pooled samples in farm A, using 100 EPG as threshold, no justification for treatment was seen throughout the experimental period. However, on farm B values of 100 EPG were seen at 9 and 11, 13 and 14 and 14 weeks after ivermectin treatment in pools 10, 12 and 13, respectively. This coincided with the presence of one or two horses with egg counts above 200 EPG. The conclusion is that random pooled faecal samples of 10 adult horses from a larger herd, starting at the ERP and repeating it at, for instance, 4-week intervals, could be used for decisions on worm control. However, there would be a certain risk for underestimating pasture contamination through missing high-egg excreters. An alternative use of pooled samples would be as a cheap first screening to detect which adult horses really contribute to pasture contamination with worm eggs on a farm. All horses should be sampled and subsequently animals from 'positive' pools can be reexamined individually.

Currently used traffic control measures, such as traffic signals, variable speed limits, ramp metering installations etc., are often not designed to influence the route choice of drivers. However, traffic control measures do influence the travel times that are experienced in the network. Since route choice is, at least for a part, based on experienced travel times, the control measures thus also influence the long-term route choice. This influence can be seen as a side-effect of the control measures, but in this paper we will investigate the possibilities to explicitly and actively use the influence of the traffic control measures to change the long-term route choice. Using basic traffic flow and route choice models we investigate how outflow and speed limit control can affect the final equilibrium turning fractions. As an example we consider a case study for a simple network with two routes and use a simple linear outflow controller, which makes the analytical investigation of the effects of the controller possible, but the results can be extended to more sophisticated control methods.

Humans are exposed to a variety of food-borne phytochemicals (PC) as well as synthetic chemicals (SC). Some of these compounds have been reported to have estrogenic or anti-estrogenic properties and are therefore suspected endocrine disruptors. Until now it remains unclear if non-additive effects occur in combinations with endogenous estrogens, such as 17beta-estradiol (E(2)). To investigate such interactions, several PC and SC were tested individually, in mixtures and as combinations of mixtures with E(2) for effects on ERalpha receptor mediated cell proliferation and estrogen regulated pS2 expression level in MCF-7(bus) cells. PCs (coumestrol, genistein, naringenin, catechin, epicatechin, quercetin) or SCs (4-nonylphenol, octylphenol, beta-hexachlorocyclohexane, bisphenol A, methoxychlor, dibutyl phthalate) were mixed (PCmix and SCmix) either in concentrations reflecting human serum concentrations or at equipotent concentrations for estrogenicity. EC(50) values were applied in two approaches of the concentration-addition model (the method of isoboles and the cumulative estrogen equivalency method) to assess mixture effects. In both models PCmix and SCmix or combinations of the mixtures with E(2) showed no departure from additivity. In conclusion, the tested PCs and SCs appeared to act as (full) agonists for the estrogen receptor and interacted in mixtures and with estradiol in an additive way. In addition, it is concluded that the possible contribution of food-borne PCs to the estrogenic effect of xenobiotics is likely to be more significant than that caused by food-borne SCs.