Pediatric Cardiology Fellowship Standards for Training in Exercise Medicine and Curriculum Outline.

Over the past 2 decades, fundamentals of exercise medicine, including clinical exercise testing, assessment and promotion of physical activity, exercise prescription, and supervised exercise training/rehabilitation programming have demonstrated considerable clinical value in the management of children and adolescents with congenital and acquired heart disease. Although the principles of exercise medicine have become an integral component in pediatric cardiology, there are no standardized training recommendations for exercise physiology during pediatric cardiology fellowship at this time. Thus, the Pediatric Cardiology Exercise Medicine Curriculum Committee (PCEMCC) was formed to establish core and advanced exercise physiology training recommendations for pediatric cardiology trainees. The PCEMCC includes a diverse group of pediatric cardiologists, exercise physiologists, and fellowship program directors. The expert consensus training recommendations are by no means a mandate and are summarized herein, including suggestions for achieving the minimum knowledge and training needed for general pediatric cardiology practice.

The impacts of changing climate and streamflow on nutrient speciation in a large Prairie reservoir.

Climate mediated warming water temperature, drought and extreme flooding are projected to shift the phenology of nutrients in receiving lakes and reservoirs further intensifying eutrophication and algal blooms, especially in temperate reservoirs. An emerging issue in reservoir management is the prediction of climate change impacts, a necessity for sound decision making and sustainable management. Lake Diefenbaker is a large multipurpose reservoir in the Canadian Prairies. In this study, the impact of climate change on nutrient speciation in Lake Diefenbaker is examined using loosely linked SpAtially Referenced Regression On Watershed attributes (SPARROW) and CE-QUAL-W2 models. Two climate mediated scenarios, RCP 8.5 representing the most extreme climate change, and climate induced streamflow were modelled. Nutrient levels are anticipated to double under the climate change and streamflow scenarios. Winter and spring were identified as hot moments for nitrogen pollution with a plausible saturation of nitrous oxides in the future. Of concern is a plausible recycling of nitrate through dissimilatory nitrate reduction to ammonium. Summer and fall on the other hand represent the period for phosphorus enrichment and internal loading with a probable succession of cyanobacteria in the summer.

Self-harm and violent criminality linked with parental death during childhood.

BACKGROUND: Adverse health and social outcomes are known to occur more frequently following parental death during childhood, but evidence is lacking for comparing long-term risks of internalised v. externalised harm. METHODS: This national register-based cohort study consisted of Danish persons born 1970-2000. The Civil Registration System and National Causes of Death Register were linked to ascertain parental deaths by cause before cohort members' 15th birthdays. From age 15 years, hospital-treated self-harm episodes were ascertained through linkage to the National Patient Register and the Psychiatric Central Research Register, and violent crimes were identified via linkage to the National Crime Register. Hazard ratio and cumulative incidence values were estimated. RESULTS: Self-harm and violent criminality risks were elevated following parental death during childhood. Covariate adjustment for gender, birth year and first-degree relatives' mental illnesses attenuated these associations, although significantly heightened risks persisted. The estimated hazard ratios did not differ greatly according to which parent died, but losing both parents conferred particularly large risk increases. Risks for both adverse outcomes were higher in relation to unnatural v. natural parental death; violent criminality risk was especially raised among individuals exposed to parental death by unnatural causes other than suicide. The association was strongest when pre-school age children experienced parental death. CONCLUSIONS: Effective early intervention is needed to help youngsters who have experienced the death of one or both parents to develop immediate and sustained coping strategies. Enhanced cooperation between health and social services and criminal justice agencies may mitigate risks for these two destructive behaviours.

Psychiatric morbidity and suicidal behaviour in psoriasis: a primary care cohort study.

BACKGROUND: Psychological distress among people with psoriasis may lead to elevated risks of suicide and nonfatal self-harm. OBJECTIVES: To investigate psychiatric comorbidity, psychotropic medication prescribing and risk of suicidality in people with psoriasis. METHODS: A cohort of patients with psoriasis (1998-2014) was delineated using the Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics and Office for National Statistics mortality records. Each patient with psoriasis was matched with up to 20 patients without psoriasis on age, sex and general practice. A stratified Cox regression model was used to estimate the hazard ratios (HRs) for suicide or nonfatal self-harm risks adjusted for socioeconomic status. RESULTS: At baseline, among 56 961 and 876 919 patients with and without psoriasis, higher prevalence for histories of alcohol misuse, bipolar disorder, depression, anxiety disorders, self-harm and psychotropic drug prescription were observed. The deprivation-adjusted HR indicated lower suicide risk in people with psoriasis [HR 0·59, 95% confidence interval (CI) 0·41-0·85]. The risk of suicide varied according to age: it was lower in people with psoriasis diagnosed at ≥ 40 years (HR 0·38, 95% CI 0·21-0·66), whereas there was no difference in risk of suicide in people with psoriasis diagnosed before age 40 years (HR 0·92, 95% CI 0·58-1·46). Conversely, there was a small increased risk for self-harm (HR 1·15, 95% CI 1·04-1·27) associated with psoriasis. CONCLUSIONS: The prevalence of mental illness was raised in people with psoriasis, and this may lead to a greater risk of self-harm. Nevertheless, having psoriasis does not appear to be associated with an increased risk of suicide. Healthcare professionals caring for patients with psoriasis should continue to monitor and tackle effectively the psychological needs of these individuals.

Advances in non-contrast quiescent-interval slice-selective (QISS) magnetic resonance angiography.

There is a pressing clinical need to develop accurate, efficient non-contrast magnetic resonance angiography (NC-MRA) techniques. Our efforts in the field have focused on a novel non-subtractive technique called quiescent-interval slice-selective (QISS) MRA. Compared with other NC-MRA techniques, QISS has the advantage of being more accurate while enabling a simpler and more efficient workflow. The original implementation, which uses electrocardiogram (ECG) gating and a Cartesian k-space trajectory, is a reliable technique for the evaluation of peripheral arterial disease (PAD). Recent advances in QISS technology include the use of a radial k-space trajectory, which facilitates rapid imaging of the coronary, renal, and pulmonary arteries as well as other vascular beds, and ungated ("UnQISS") acquisitions for PAD.

Routine hospital management of self-harm and risk of further self-harm: propensity score analysis using record-based cohort data.

BACKGROUND: The care received by people presenting to hospital following self-harm varies and it is unclear how different types of treatment affect risk of further self-harm. METHOD: Observational cohort data from the Manchester Self-Harm Project, UK, included 16 456 individuals presenting to an Emergency Department with self-harm between 2003 and 2011. Individuals were followed up for 12 months. We also used data from a smaller cohort of individuals presenting to 31 hospitals in England during a 3-month period in 2010/2011, followed up for 6 months. Propensity score (PS) methods were used to address observed confounding. Missing data were imputed using multiple imputation. RESULTS: Following PS stratification, those who received a psychosocial assessment had a lower risk of repeat hospital attendance for self-harm than those who were not assessed [RR 0.87, 95% confidence interval (CI) 0.80-0.95]. The risk was reduced most among people less likely to be assessed. Following PS matching, we found no associations between risks of repeat self-harm and admission to a medical bed, referral to outpatient psychiatry or admission to a psychiatric bed. We did not find a relationship between psychosocial assessment and repeat self-harm in the 31 centre cohort. CONCLUSIONS: This study shows the potential value of using novel statistical techniques in large mental health datasets to estimate treatment effects. We found that specialist psychosocial assessment may reduce the risk of repeat self-harm. This type of routine care should be provided for all individuals who present to hospital after self-harm, regardless of perceived risk.

Suicide risk linked with clinical consultation frequency, psychiatric diagnoses and psychotropic medication prescribing in a national study of primary-care patients.

BACKGROUND: Little is known about the precursors of suicide risk among primary-care patients. This study aimed to examine suicide risk in relation to patterns of clinical consultation, psychotropic drug prescribing, and psychiatric diagnoses. METHOD: Nested case-control study in the Clinical Practice Research Datalink (CPRD), England. Patients aged ⩾16 years who died by suicide during 2002-2011 (N = 2384) were matched on gender, age and practice with up to 20 living control patients (N = 46 899). RESULTS: Risk was raised among non-consulting patients, and increased sharply with rising number of consultations in the preceding year [⩾12 consultations v. 1: unadjusted odds ratio (OR) 6.0, 95% confidence interval (CI) 4.9-7.3]. Markedly elevated risk was also associated with the prescribing of multiple psychotropic medication types (⩾5 types v. 0: OR 62.6, CI 44.3-88.4) and with having several psychiatric diagnoses (⩾4 diagnoses v. 0: OR 31.1, CI 19.3-50.1). Risk was also raised among patients living in more socially deprived localities. The confounding effect of multiple psychotropic drug types largely accounted for the rising risk gradient observed with increasing consultation frequency. CONCLUSIONS: A greater proportion of patients with several psychiatric diagnoses, those prescribed multiple psychotropic medication types, and those who consult at very high frequency might be considered for referral to mental health services by their general practitioners. Non-consulters are also at increased risk, which suggests that conventional models of primary care may not be effective in meeting the needs of all people in the community experiencing major psychosocial difficulties.

Overnight improvements in two REM sleep-sensitive tasks are associated with both REM and NREM sleep changes, sleep spindle features, and awakenings for dream recall.

Memory consolidation is associated with sleep physiology but the contribution of specific sleep stages remains controversial. To clarify the contribution of REM sleep, participants were administered two REM sleep-sensitive tasks to determine if associated changes occurred only in REM sleep. Twenty-two participants (7 men) were administered the Corsi Block Tapping and Tower of Hanoi tasks prior to and again after a night of sleep. Task improvers and non-improvers were compared for sleep structure, sleep spindles, and dream recall. Control participants (N = 15) completed the tasks twice during the day without intervening sleep. Overnight Corsi Block improvement was associated with more REM sleep whereas Tower of Hanoi improvement was associated with more N2 sleep. Corsi Block improvement correlated positively with %REM sleep and Tower of Hanoi improvement with %N2 sleep. Post-hoc analyses suggest Tower of Hanoi effects-but not Corsi Block effects-are due to trait differences. Sleep spindle density was associated with Tower of Hanoi improvement whereas spindle amplitude correlated with Corsi Block improvement. Number of REM awakenings for dream reporting (but not dream recall per se) was associated with Corsi Block, but not Tower of Hanoi, improvement but was confounded with REM sleep time. This non-replication of one of 2 REM-sensitive task effects challenges both 'dual-process' and 'sequential' or 'sleep organization' models of sleep-dependent learning and points rather to capacity limitations on REM sleep. Experimental awakenings for sampling dream mentation may not perturb sleep-dependent learning effects; they may even enhance them.

Efficacy and tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5.

AIMS: To investigate the efficacy and tolerability of albiglutide, a weekly glucagon-like peptide-1 receptor agonist, when added to metformin and glimepiride in a triple therapy regimen in people with type 2 diabetes mellitus. METHODS: This was a 156-week, randomized, double-blind, parallel-group, multicentre study. In the present paper we describe the primary results, namely those at 52 weeks. Adult participants (n = 685) were randomly assigned to albiglutide (30 mg/week), pioglitazone (30 mg/day) or placebo. If needed, blinded uptitration of albiglutide (to 50 mg/week) and pioglitazone (to 45 mg/day) was allowed. The participant's current dose of metformin (>1500 mg/day) was maintained throughout. The glimepiride dose (4 mg/day), standardized before randomization, could be decreased if persistent hypoglycaemia occurred. RESULTS: The week 52 model-adjusted difference in change of glycated haemoglobin (primary endpoint) for albiglutide versus placebo was -0.87 [95% confidence interval (CI) -1.07, -0.68]%-units (p < 0.001), and for albiglutide versus pioglitazone it was 0.25 (95% CI 0.10, 0.40)%-units; therefore, not non-inferior. In the albiglutide group only, fasting plasma glucose reduced rapidly in the first 2 weeks. Confirmed hypoglycaemia occurred in 14% of participants on albiglutide, 25% on pioglitazone and 14% on placebo. The mean (± standard error) weight change was -0.42 (±0.2) kg with albiglutide, +4.4 (±0.2) kg (p < 0.001) with pioglitazone, and -0.40 (±0.4) kg with placebo and serious adverse events occurred in 6.3, 9.0 and 6.1% of participants in the respective groups. Injection site reactions occurred in 13% of participants on albiglutide and resulted in treatment discontinuation for four participants (1.4%). CONCLUSIONS: Albiglutide, as part of triple therapy, provided effective glucose-lowering and was generally well tolerated.

Albiglutide does not impair the counter-regulatory hormone response to hypoglycaemia: a randomized, double-blind, placebo-controlled, stepped glucose clamp study in subjects with type 2 diabetes mellitus.

AIM: To determine if the glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide, once weekly, impairs counter-regulatory responses during hypoglycaemia. METHODS: We conducted a randomized, double-blind, parallel, placebo-controlled study in subjects with type 2 diabetes mellitus. A single dose of albiglutide 50 mg (n = 22) or placebo (n = 22) was administered on day 1. Glucose was clamped on day 4 (to coincide with the approximate albiglutide maximum plasma concentration) at 9.0, 5.0, 4.0, 3.3 and 2.8 mmol/l (162, 90, 72, 59.4 and 50.4 mg/dl), with a post-clamp recovery period to 3.9 mmol/l (70 mg/dl). Hormone measurements were made at each plateau and adverse events (AEs) were recorded. RESULTS: The counter-regulatory hormones glucagon, epinephrine, norepinephrine, growth hormone and cortisol were appropriately suppressed when plasma glucose levels were >4.0 mmol/l (>72 mg/dl), but increased in the albiglutide and placebo groups with glucose levels <3.3 mmol/l (<59.4 mg/dl) in response to hypoglycaemia. The area under the curve geometric mean ratios (albiglutide : placebo), calculated from the clamped plateau of 4.0 mmol/l (72 mg/dl) to the glucose recovery point, were not significantly different for any of the counter-regulatory hormones. When plasma glucose levels were >5.0 mmol/l (>90 mg/dl), albiglutide increased pancreatic ß-cell secretion of C-peptide in a glucose-dependent manner to a greater extent than did placebo, and it was suppressed in each group when levels were <4.0 mmol/l (<72 mg/dl). No significant difference between groups was observed in the recovery time to glucose level ≥3.9 mmol/l (≥70 mg/dl). There were no clinically relevant differences in AEs or other safety variables. CONCLUSIONS: A single 50-mg dose of albiglutide was well tolerated and did not impair the counter-regulatory response to hypoglycaemia. These data provide mechanistic evidence supporting the low intrinsic hypoglycaemic potential of albiglutide.

Lack of seasonal variation in bleeding and patient-assessed pain patterns in patients with haemophilia B receiving on-demand therapy.

Spontaneous haemorrhage in patients with haemophilia is generally considered to occur randomly and without a predictable temporal or seasonal pattern; however, there is a lack of evidence in the literature on the effects of weather, temperature and atmosphere on bleeding episodes. This post hoc analysis of a multicentre, open-label crossover study examined the influence of seasonality on bleeding frequency and patient-assessed pain in patients with moderately severe and severe (FIX C ≤ 2%) haemophilia B. Fifty patients were enrolled and treated on-demand for 16 weeks; 47 were subsequently randomized to one of two prophylactic regimens (nonacog alfa 100 IU kg(-1) once weekly or 50 IU kg(-1) twice weekly) for 16 weeks. Patients then underwent an 8-week washout period of on-demand therapy before being crossed over to the other prophylactic regimen for 16 weeks. Bleeding episodes during the on-demand treatment periods were analysed. To assess for temporal trends, data were graphed as scatter plots. The primary end point was the annualized bleeding rate (ABR). Additional measures included raw and median pain scores during every joint bleeding event (spontaneous or traumatic), with pain scored using the Brief Pain Inventory (0 = 'no pain' to 10 = 'pain as bad as you can imagine'). The observed ABRs during the on-demand periods showed no distinguishable trend over time. Analysis of pain associated with joint bleeding episodes also did not demonstrate any discernible temporal trend. No apparent seasonal variation in bleeding pattern or patient-reported pain was observed in this analysis of patients with haemophilia B.

Fecal Bacteria Contamination of Floodwaters and a Coastal Waterway From Tidally-Driven Stormwater Network Inundation.

Inundation of coastal stormwater networks by tides is widespread due to sea-level rise (SLR). The water quality risks posed by tidal water rising up through stormwater infrastructure (pipes and catch basins), out onto roadways, and back out to receiving water bodies is poorly understood but may be substantial given that stormwater networks are a known source of fecal contamination. In this study, we (a) documented temporal variation in concentrations of Enterococcus spp. (ENT), the fecal indicator bacteria standard for marine waters, in a coastal waterway over a 2-month period and more intensively during two perigean spring tide periods, (b) measured ENT concentrations in roadway floodwaters during tidal floods, and (c) explained variation in ENT concentrations as a function of tidal inundation, antecedent rainfall, and stormwater infrastructure using a pipe network inundation model and robust linear mixed effect models. We find that ENT concentrations in the receiving waterway vary as a function of tidal stage and antecedent rainfall, but also site-specific characteristics of the stormwater network that drains to the waterway. Tidal variables significantly explain measured ENT variance in the waterway, however, runoff drove higher ENT concentrations in the receiving waterway. Samples of floodwaters on roadways during both perigean spring tide events were limited, but all samples exceeded the threshold for safe public use of recreational waters. These results indicate that inundation of stormwater networks by tides could pose public health hazards in receiving water bodies and on roadways, which will likely be exacerbated in the future due to continued SLR.

High morbidity and mortality associated with an outbreak of influenza A(H3N2) in a psycho-geriatric facility.

In spring 2008, an influenza A subtype H3N2 outbreak occurred in a long stay psycho-geriatric ward and two wards in the intellectual disability services (IDS), part of a large psychiatric hospital. The attack rate in the index ward was 90% (18/20) for patients and 35% (7/20) for staff. It was 14% (1/7) and 17% (2/12) in the affected IDS wards for patients and 0% (0/20) and 4% (1/25) for staff. Many of the laboratory-confirmed cases did not have a fever >38 °C, a typical sign of influenza. Control measures included oseltamivir treatment for cases and prophylaxis for contacts, standard and droplet infection control precautions, active surveillance for early detection and isolation of potential cases. As a result, the outbreak did not spread throughout the hospital. Although the staff vaccination rate (10%) prior to the outbreak was low, we observed a much lower vaccine effectiveness rate in the patients (11%) than in the staff (100%) in the index ward. Vaccination of residents and staff of such facilities remains the key influenza prevention strategy.

A method for beam's eye view breath-hold monitoring during breast volumetric modulated arc therapy.

Background and purpose: Deep inspiration breath-hold (DIBH) is a technique that is widely utilised to spare the heart and lungs during breast radiotherapy. In this study, a method was developed to validate directly the intrafraction accuracy of DIBH during breast volumetric modulated arc therapy (VMAT) via internal chest wall (CW) monitoring. Materials and methods: In-house software was developed to automatically extract and compare the treatment position of the CW in cine-mode electronic portal image device (EPID) images with the planned CW position in digitally reconstructed radiographs (DRR) for breast VMAT treatments. Feasibility of this method was established by evaluating the percentage of total dose delivered to the target volume when the CW was sufficiently visible for monitoring. Geometric accuracy of the approach was quantified by applying known displacements to an anthropomorphic thorax phantom. The software was used to evaluate (offline) the geometric treatment accuracy for ten patients treated using real-time position management (RPM)-guided DIBH. Results: The CW could be monitored within the tangential sub-arcs which delivered a median 89% (range 73% to 97%) of the dose to target volume. The phantom measurements showed a geometric accuracy within 1 mm, with visual inspection showing good agreement between the software-derived and user-determined CW positions. For the RPM-guided DIBH treatments, the CW was found to be within ±5 mm of the planned position in 97% of EPID frames in which the CW was visible. Conclusion: An intrafraction monitoring method with sub-millimetre accuracy was successfully developed to validate target positioning during breast VMAT DIBH.

Absolute risks of self-harm and interpersonal violence by diagnostic category following first discharge from inpatient psychiatric care.

BACKGROUND: Persons discharged from inpatient psychiatric services are at greatly elevated risk of harming themselves or inflicting violence on others, but no studies have reported gender-specific absolute risks for these two outcomes across the spectrum of psychiatric diagnoses. We aimed to estimate absolute risks for self-harm and interpersonal violence post-discharge according to gender and diagnostic category. METHODS: Danish national registry data were utilized to investigate 62,922 discharged inpatients, born 1967-2000. An age and gender matched cohort study was conducted to examine risks for self-harm and interpersonal violence at 1 year and at 10 years post-discharge. Absolute risks were estimated as cumulative incidence percentage values. RESULTS: Patients diagnosed with substance misuse disorders were at especially elevated risk, with the absolute risks for either self-harm or interpersonal violence being 15.6% (95% CI 14.9, 16.3%) of males and 16.8% (15.6, 18.1%) of females at 1 year post-discharge, rising to 45.7% (44.5, 46.8%) and 39.0% (37.1, 40.8%), respectively, within 10 years. Diagnoses of personality disorders and early onset behavioral and emotional disorders were also associated with particularly high absolute risks, whilst risks linked with schizophrenia and related disorders, mood disorders, and anxiety/somatoform disorders, were considerably lower. CONCLUSIONS: Patients diagnosed with substance misuse disorders, personality disorders and early onset behavioral and emotional disorders are at especially high risk for internally and externally directed violence. It is crucial, however, that these already marginalized individuals are not further stigmatized. Enhanced care at discharge and during the challenging transition back to life in the community is needed.

Use of a geographic information system to map cases of measles in real-time during an outbreak in Dublin, Ireland, 2011.

In 2011, there was a large measles outbreak in Dublin. Nationally 285 cases were notified to the end of December 2011, and 250 (88%) were located in the Dublin region. After the first case was notified in week 6, numbers gradually increased, with 25 notified in June and a peak of 53 cases in August. Following public health intervention including a measles-mumps-rubella (MMR) vaccination campaign, no cases were reported in the Dublin region in December 2011. Most cases (82%) were children aged between 6 months and 14 years, and 46 cases (18%) were under 12 months-old. This is the first outbreak in Dublin to utilise a geographic information system for plotting measles cases on a digital map in real time. This approach, in combination with the analysis of case notifications, assisted the department of public health in demonstrating the extent of the outbreak. The digital mapping documented the evolution of two distinct clusters of 87 (35%) cases. These measles cases were infected with genotype D4-Manchester recently associated with large outbreaks across Europe. The two clusters occurred in socio-economically disadvantaged areas and were attributable to inadequate measles vaccination coverage due in part to the interruption of a school-based MMR2 vaccination programme.

Suicide and death by other causes among patients with a severe mental illness: cohort study comparing risks among patients discharged from inpatient care v. those treated in the community.

AIMS: People diagnosed with a severe mental illness (SMI) are at elevated risk of dying prematurely compared to the general population. We aimed to understand the additional risk among people with SMI after discharge from inpatient psychiatric care, when many patients experience an acute phase of their illness. METHODS: In the Clinical Practice Research Datalink (CPRD) GOLD and Aurum datasets, adults aged 18 years and older who were discharged from psychiatric inpatient care in England between 2001 and 2018 with primary diagnoses of SMI (schizophrenia, bipolar disorder, other psychoses) were matched by age and gender with up to five individuals with SMI and without recent hospital stays. Using survival analysis approaches, cumulative incidence and adjusted hazard ratios were estimated for all-cause mortality, external and natural causes of death, and suicide. All analyses were stratified by younger, middle and older ages and also by gender. RESULTS: In the year after their discharge, the risk of dying by all causes examined was higher than among individuals with SMI who had not received inpatient psychiatric care recently. Suicide risk was 11.6 times (95% CI 6.4-20.9) higher in the first 3 months and remained greater at 2-5 years after discharge (HR 2.3, 1.7-3.2). This risk elevation remained after adjustment for self-harm in the 6 months prior to the discharge date. The relative risk of dying by natural causes was raised in the first 3 months (HR 1.6, 1.3-1.9), with no evidence of elevation during the second year following discharge. CONCLUSIONS: There is an additional risk of death by suicide and natural causes for people with SMI who have been recently discharged from inpatient care over and above the general risk among people with the same diagnosis who have not recently been treated as an inpatient. This mortality gap shows the importance of continued focus, following discharge, on individuals who require inpatient care.

Monitoring rFVIIa 90 µg kg⁻¹ dosing in haemophiliacs: comparing laboratory response using various whole blood assays over 6 h.

Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 µg kg⁻¹. Ten non-bleeding subjects with severe FVIII or FIX deficiency were infused with a single-dose of rFVIIa 90 µg k⁻¹ body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half-life of factor FVII:C was estimated as 39.0 ± 8.8 mL h⁻¹ kg⁻¹ and 2.1 ± 0.2 h respectively. There was good inter-assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P < 0.0001), and these parameters were dynamic throughout the 6-h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P < 0.001), but remained steady throughout the study. There was no change in D-dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study.

Tropical to mid-latitude snow and ice accumulation, flow and glaciation on Mars.

Images from the Mars Express HRSC (High-Resolution Stereo Camera) of debris aprons at the base of massifs in eastern Hellas reveal numerous concentrically ridged lobate and pitted features and related evidence of extremely ice-rich glacier-like viscous flow and sublimation. Together with new evidence for recent ice-rich rock glaciers at the base of the Olympus Mons scarp superposed on larger Late Amazonian debris-covered piedmont glaciers, we interpret these deposits as evidence for geologically recent and recurring glacial activity in tropical and mid-latitude regions of Mars during periods of increased spin-axis obliquity when polar ice was mobilized and redeposited in microenvironments at lower latitudes. The data indicate that abundant residual ice probably remains in these deposits and that these records of geologically recent climate changes are accessible to future automated and human surface exploration.

Molecular phylogeny of choanoflagellates, the sister group to Metazoa.

Choanoflagellates are single-celled aquatic flagellates with a unique morphology consisting of a cell with a single flagellum surrounded by a "collar" of microvilli. They have long interested evolutionary biologists because of their striking resemblance to the collared cells (choanocytes) of sponges. Molecular phylogeny has confirmed a close relationship between choanoflagellates and Metazoa, and the first choanoflagellate genome sequence has recently been published. However, molecular phylogenetic studies within choanoflagellates are still extremely limited. Thus, little is known about choanoflagellate evolution or the exact nature of the relationship between choanoflagellates and Metazoa. We have sequenced four genes from a broad sampling of the morphological diversity of choanoflagellates including most species currently available in culture. Phylogenetic analyses of these sequences, alone and in combination, reject much of the traditional taxonomy of the group. The molecular data also strongly support choanoflagellate monophyly rejecting proposals that Metazoa were derived from a true choanoflagellate ancestor. Mapping of a complementary matrix of morphological and ecological traits onto the phylogeny allows a reinterpretation of choanoflagellate character evolution and predicts the nature of their last common ancestor.