The signature of competition in ecomorphological traits across the avian radiation.

Competition for shared resources represents a fundamental driver of biological diversity. However, the tempo and mode of phenotypic evolution in deep-time has been predominantly investigated using trait evolutionary models which assume that lineages evolve independently from each other. Consequently, the role of species interactions in driving macroevolutionary dynamics remains poorly understood. Here, we quantify the prevalence for signatures of competition between related species in the evolution of ecomorphological traits across the bird radiation. We find that mechanistic trait models accounting for the effect of species interactions on phenotypic divergence provide the best fit for the data on at least one trait axis in 27 out of 59 clades ranging between 21 and 195 species. Where it occurs, the signature of competition generally coincides with positive species diversity-dependence, driven by the accumulation of lineages with similar ecologies, and we find scarce evidence for trait-dependent or negative diversity-dependent phenotypic evolution. Overall, our results suggest that the footprint of interspecific competition is often eroded in long-term patterns of phenotypic diversification, and that other selection pressures may predominantly shape ecomorphological diversity among extant species at macroevolutionary scales.

A comparison of drug substance predicted chemical stability with ICH compliant stability studies.

OBJECTIVE: The aim of this study is to demonstrate the applicability of predictive stability studies to the degradation of drug substances. SIGNIFICANCE: The use of predicted stability studies during pharmaceutical development and in regulatory submissions is increasing, particularly in early phase to support an initial retest period/shelf life claim in the absence of standard stability data. These studies offer an alternative to standard stability testing and can facilitate clinical trials to be started earlier and medicines to reach patients faster. They involve a short-term stressed stability study, typically designed to degrade a drug substance or product to the specification level of the shelf life limiting attribute. The results are used to predict degradation under long-term storage conditions and enable stability understanding to be gained over a short time frame, using limited amounts of material. METHODS: In this work, Accelerated Stability Assessment Program (ASAP) studies were performed for 10 different drug substances and the predictions obtained for chemical degradation were compared to ICH compliant stability data. RESULTS: Across the studies good agreement was achieved, with the initial retest period predictions from the ASAP studies being conservative by design. When minimal degradation was observed during an ASAP study, it was demonstrated that at least a 12-month initial retest period could be supported. CONCLUSION: This comparison of ASAP predictions and ICH compliant stability data has demonstrated the ability of well-designed ASAP studies to predict the long-term chemical stability of drug substances.

Correlates of rate heterogeneity in avian ecomorphological traits.

Heterogeneity in rates of trait evolution is widespread, but it remains unclear which processes drive fast and slow character divergence across global radiations. Here, we test multiple hypotheses for explaining rate variation in an ecomorphological trait (beak shape) across a globally distributed group (birds). We find low support that variation in evolutionary rates of species is correlated with life history, environmental mutagenic factors, range size, number of competitors, or living on islands. Indeed, after controlling for the negative effect of species' age, 80% of variation in species-specific evolutionary rates remains unexplained. At the clade level, high evolutionary rates are associated with unusual phenotypes or high species richness. Taken together, these results imply that macroevolutionary rates of ecomorphological traits are governed by both ecological opportunity in distinct adaptive zones and niche differentiation among closely related species.

Patent ductus arteriosus in cats (Felis catus): 50 cases (2000-2015).

OBJECTIVES: To describe signalment, clinical characteristics, diagnostic, treatment, and outcome data in a large case series of cats with patent ductus arteriosus (PDA). ANIMALS: Fifty cats with confirmed PDA. METHODS: Retrospective review of medical records from five referral veterinary hospitals for cats with PDA between 2000 and 2015. Cats were included if a PDA was visualized echocardiographically, during surgery, or on post-mortem examination. RESULTS: Median age at presentation was 6 months (range: 36 days-9.7 years; n = 50), and sex distribution was approximately equal (27 male, 23 female). Most cats did not have clinical signs (70.2%; 33/47) at the time of presentation. Murmurs were classified as continuous (55%; 22/40) or systolic (45%; 18/40). Echocardiography confirmed left-to-right shunting in 33 cats (82.5%; 33/40) and right-to-left shunting in 7 (17.5%; 7/40). Concurrent cardiac anomalies were identified in 54.5% (18/33) and pulmonary hypertension in 45.7% (16/35). Closure was pursued in 68% (34/50), and complications associated with the procedure occurred in 14.7% (5/34) of cats, including one intraoperative mortality. Long-term follow up was available in 80% (40/50) of cats. CONCLUSIONS: Cats with PDA often do not display clinical signs and may not have the characteristic physical examination findings typical of PDA in dogs. An increased prevalence of concurrent cardiac anomalies and pulmonary hypertension were found relative to previous reports. Thoracic radiographs and echocardiogram may provide the most comprehensive information for making a diagnosis and treatment recommendations. PDA closure was associated with a favorable long-term outcome in cats included in this study.

Palliative balloon dilation of pulmonic stenosis in a dog with tetralogy of Fallot.

A 6-month-old Beagle with tetralogy of Fallot underwent balloon valvuloplasty of the pulmonary valve. Balloon valvuloplasty was successful and resulted in palliation of clinical signs and an improved quality of life for approximately 9 months. After 9 months, the dog became symptomatic and a modified Blalock-Taussig shunt procedure was successfully performed. Based on this report, balloon valvuloplasty in dogs with tetralogy of Fallot appears to be a feasible technique that may result in improvement of clinical signs. In addition, it may allow for the delay of the more invasive surgical palliation and provide time for weight gain and development of the pulmonary vascular bed for greater ease of surgical shunt creation.

Pathologic and cardiovascular characterization of pheochromocytoma-associated cardiomyopathy in dogs.

Pheochromocytoma-associated catecholamine-induced cardiomyopathy is a well-known entity in man, nonhuman primates, and mice but has not been described in dogs. In this retrospective study, 9 dogs were identified with pheochromocytomas and concurrent cardiovascular pathology observed histologically (n = 6), echocardiographically (n = 4), and/or electrocardiographically (n = 5). Cardiac lesions included multifocal cardiomyocyte necrosis with contraction bands, cardiomyocyte degeneration, myocardial hemorrhage, lymphohistiocytic myocarditis, and interstitial fibrosis. Clinical procedures, including electrocardiographic and echocardiographic examinations, Doppler blood pressure measurement, and auscultation, were available for 5 dogs and consistently revealed concentric or mixed (eccentric and concentric) ventricular hypertrophy. Additional changes observed included arrhythmias, systemic hypertension, and heart murmurs. The myocardial lesions observed in this series of dogs are similar to those observed in humans with pheochromocytoma-associated catecholamine-induced cardiomyopathy. Since the clinical manifestations of catecholamine-induced cardiac disease are amenable to medical treatment, recognition of this cardiomyopathy has the potential to reduce morbidity and mortality in dogs with pheochromocytoma.

Echocardiographic findings in 11 cats with acromegaly.

BACKGROUND: Information regarding cardiac changes in domestic cats with acromegaly is limited. HYPOTHESIS/OBJECTIVES: The objective of this study was to describe the echocardiographic findings in cats with acromegaly. ANIMALS: Eighteen cats diagnosed with acromegaly at Colorado State University between 2008 and 2012. Of these 18 cats, 11 had echocardiography performed. METHODS: A retrospective review of medical records was made to identify cats with acromegaly that also had echocardiography performed. RESULTS: Of the 11 cats identified, 7 had left ventricular concentric hypertrophy, 6 had left atrial enlargement, and 7 had evidence of abnormal diastolic function. All 11 cats had evidence of structural or functional cardiac disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Cardiovascular abnormalities frequently are present in cats with acromegaly, and a complete cardiac evaluation should be considered in these patients.

An illustration of the effect of various sources of uncertainty on DNA likelihood ratio calculations.

A typical assessment of the strength of forensic DNA evidence is based on a population genetic model and estimated allele frequencies determined from a population database. Some experts provide a confidence or credible interval which takes into account the sampling variation inherent in deriving these estimates from only a sample of a total population. This interval is given in conjunction with the statistic of interest, be it a likelihood ratio (LR), match probability, or cumulative probability of inclusion. Bayesian methods of addressing database sampling variation produce a distribution for the statistic from which the bound(s) of the desired interval can be determined. Population database sampling uncertainty represents only one of the sources of uncertainty that affects estimation of the strength of DNA evidence. There are other uncertainties which can potentially have a much larger effect on the statistic such as, those inherent in the value of Fst, the weights given to genotype combinations in a continuous interpretation model, and the composition of the relevant population. In this paper we model the effect of each of these sources of uncertainty on a likelihood ratio (LR) calculation and demonstrate how changes in the distribution of these parameters affect the reported value. In addition, we illustrate the impact the different approaches of accounting for sampling uncertainties has on the LR for a four person mixture.

Doppler echocardiographic evaluation of midventricular obstruction in cats with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is heterogeneous in both people and cats, with variability in the distribution of hypertrophy, hemodynamic characteristics, and Doppler echocardiographic findings. OBJECTIVES: To document the Doppler echocardiographic characteristics of midventricular obstruction in some cats with HCM. ANIMALS: Eight cats with hypertrophic cardiomyopathy. MATERIALS AND METHODS: Retrospective case series. The medical records of cats presenting to the cardiology service at Colorado State University between February 2009 and January 2012 were reviewed. All cats had a physical examination; Doppler systolic blood pressure measurement; and transthoracic two-dimensional (2D), M-mode, and Doppler echocardiography were performed. A more thorough evaluation of the echocardiographic images and measurements was performed. Cats included in this study had echocardiograms of adequate quality to confirm the diagnosis of midventricular obstruction by documentation of left midventricular concentric hypertrophy; a midventricular turbulent Doppler color flow pattern; and high velocity, late-peaking flow at the area of turbulence. Cats with evidence of systemic hypertension defined as a systolic Doppler blood pressure of greater than 170 mmHg were excluded. RESULTS: All 8 cats had left ventricular hypertrophy at the level of the papillary muscles; left, midventricular hypertrophy; and in 4/8 cats there was apical hypertrophy or basilar hypertrophy of the interventricular septum. Color flow Doppler revealed turbulent flow in 8/8 cats and spectral Doppler (continuous and pulsed wave) revealed increased flow velocities and late-peaking flow profiles at the level of the left midventricle. Two of 8 cats had a bifid midventricular flow profile in which there was a midsystolic decline in left ventricular velocities with elevated velocities extending into early diastole. The peak left ventricular outflow velocity in all 8 cats was normal. CONCLUSIONS AND CLINICAL IMPORTANCE: A variant of HCM characterized by hypertrophy at the level of the papillary muscles with midventricular obstruction is present in some cats. Recognition of this variant of feline HCM allows identification of HCM in cats with murmurs where the more classic features of HCM are not present.

Echocardiographic evidence of left ventricular hypertrophy in obese dogs.

BACKGROUND: Cardiomyopathy of obesity occurs in humans, but the gross and cellular myocardial response to obesity in dogs is not well defined. OBJECTIVES: To characterize in vivo myocardial morphology and function in normotensive obese dogs, and quantitate collagen, triglyceride and myocyte cross-sectional area (CSA) in postmortem tissues from obese dogs. ANIMALS: Echocardiographic-Doppler measurements of normotensive obese dogs (n = 19) without historical or physical examination evidence of disease, and lean healthy dogs (n = 19) matched for age and ideal weight. Postmortem data were obtained from a separate population of 4 obese and 12 lean dogs without evidence of cardiac disease. METHODS: A prospective, observational study of myocardial morphology and function was conducted by echocardiographic-Doppler measurement. Left ventricular (LV) tissue was collected for quantitation of triglyceride, collagen, and myocyte CSA. RESULTS: Compared with lean control dogs, obese dogs had increased systolic blood pressure (obese 153 ± 19 mm Hg; lean 133 ± 20 mm Hg; P = .003), and increased LV free wall thickness at end-diastole (obese 9.9 ± 1.8 mm, lean 8.7 ± 1.5 mm; P = .03) and end-systole (obese 15.2 ± 2.3 mm, lean 12.9 ± 2.3 mm; P = .004). Isovolumic relaxation time was prolonged in 7/19 (37%) of obese dogs, compared with normal ranges. Myocardial triglyceride and collagen content and myocyte CSA were similar between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: As in humans, LV hypertrophy and diastolic dysfunction can be an early myocardial change in some obese dogs.

PPARγ agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells.

BACKGROUND: Brain tumour stem cells (BTSCs) are a small population of cancer cells that exhibit self-renewal, multi-drug resistance, and recurrence properties. We have shown earlier that peroxisome proliferator-activated receptor gamma (PPARγ) agonists inhibit the expansion of BTSCs in T98G and U87MG glioma. In this study, we analysed the influence of PPARγ agonists on the expression of stemness and differentiation genes in BTSCs. METHODS: The BTSCs were isolated from T98G and DB29 glioma cells, and cultured in neurobasal medium with epidermal growth factor+basic fibroblast growth factor. Proliferation was measured by WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H-5-tetrazolio]-1,3-benzene disulphonate) and 3H thymidine uptake assays, and gene expression was analysed by quantitative reverse--transcription PCR and Taqman array. The expression of CD133, SRY box 2, and nanog homeobox (Nanog) was also evaluated by western blotting, immunostaining, and flow cytometry. RESULTS: We found that PPARγ agonists, ciglitazone and 15-deoxy-Δ(12,14)-ProstaglandinJ(2), inhibited cell viability and proliferation of T98G- and DB29-BTSCs. The PPARγ agonists reduced the expansion of CD133(+) BTSCs and altered the expression of stemness and differentiation genes. They also inhibited Sox2 while enhancing Nanog expression in BTSCs. CONCLUSION: These findings highlight that PPARγ agonists inhibit BTSC proliferation in association with altered expression of Sox2, Nanog, and other stemness genes. Therefore, targeting stemness genes in BTSCs could be a novel strategy in the treatment of glioblastoma.

Improving the validation of finite element models with quantitative full-field strain comparisons.

The techniques used to validate finite element (FE) models against experimental results have changed little during the last decades, even though the traditional approach of using single point measurements from strain gauges has major limitations: the strain distribution across the surface is not captured and the accurate determination of strain gauge positions on the model surface is difficult if the 3D surface topography of the bone surface is not measured. The full-field strain measurement technique of digital speckle pattern interferometry (DSPI) can overcome these problems, but the potential of this technique has not yet been fully exploited in validation studies. Here we explore new ways of quantifying and visualising the variation in strain magnitudes and orientations within and between repeated DSPI measurements as well as between the DSPI measurements and FEA results. We show that our approach provides a much more comprehensive and accurate validation than traditional methods. The measurement repeatability and the correspondence between measured and predicted strains vary to a great degree within and between measurement areas. The two models used in this study predict the measured strain directions and magnitudes surprisingly well considering that homogeneous and isotropic mechanical properties were assigned to the models. However, the full-field comparisons also reveal some discrepancies between measured and predicted strains that are most probably caused by inaccuracies in the models' geometries and the degree of simplification of the modelled material properties.

Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial.

BACKGROUND: Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the effects of diet and physical activity on blood pressure and glucose concentrations. METHODS: We did a randomised, controlled trial in southwest England in adults aged 30-80 years in whom type 2 diabetes had been diagnosed 5-8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A(1c)(HbA(1c)) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869. FINDINGS: Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA(1c) percentage 6·72, SD 1·02, and at 6 months 6·86, 1·02) but improved in the diet group (baseline-adjusted difference in percentage of HbA(1c) -0·28%, 95% CI -0·46 to -0·10; p=0·005) and diet plus activity group (-0·33%, -0·51 to -0·14; p<0·001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups. INTERPRETATION: An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit. FUNDING: Diabetes UK and the UK Department of Health.

Clinical and pathologic responses of American crows (Corvus brachyrhynchos) and fish crows (C ossifragus) to experimental West Nile virus infection.

West Nile virus (WNV)-associated disease has a range of clinical manifestations among avian taxa, the reasons for which are not known. Species susceptibility varies within the avian family Corvidae, with estimated mortality rates ranging from 50 to 100%. We examined and compared virologic, immunologic, pathologic, and clinical responses in 2 corvid species, the American crow (Corvus brachyrhynchos) and the fish crow (C ossifragus), following experimental WNV inoculation. Unlike fish crows, which remained clinically normal throughout the study, American crows succumbed to WNV infection subsequent to dehydration, electrolyte and pH imbalances, and delayed or depressed humoral immune responses concurrent with marked, widespread virus replication. Viral titers were approximately 3,000 times greater in blood and 30,000 to 50,000 times greater in other tissues (eg, pancreas and small intestine) in American crows versus fish crows. Histologic lesion patterns and antigen deposition supported the differing clinical outcomes, with greater severity and distribution of lesions and WNV antigen in American crows. Both crow species had multiorgan necrosis and inflammation, although lesions were more frequent, severe, and widespread in American crows, in which the most commonly affected tissues were small intestine, spleen, and liver. American crows also had inflammation of vessels and nerves in multiple tissues, including heart, kidney, and the gastrointestinal tract. WNV antigen was most commonly observed within monocytes, macrophages, and other cells of the reticuloendothelial system of affected tissues. Collectively, the data support that WNV-infected American crows experience uncontrolled systemic infection leading to multiorgan failure and rapid death.

Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells.

BACKGROUND: Brain tumours present unique challenges to conventional therapies and pose major health problems around the world. Brain tumour stem cells (BTSCs) represent a small fraction of tumour cells that maintain growth, drug resistance and recurrence properties. Constitutive androstane receptor (CAR) is a nuclear receptor transcription factor that regulates drug metabolism and homoeostasis. In this study, we examined the effect of CAR agonist, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehydeO-(3,4-dichlorobenzyl)oxime (CITCO) on BTSCs. METHODS: The expression of CAR in BTSCs was detected by quantitative RT-PCR and western blot. The antiproliferative effect of CITCO on BTSCs was determined by WST-1 and (3)H thymidine uptake assays. The effect of CITCO on CD133 expression, cell cycle progression and apoptosis in BTSCs was analysed by immunostaining and flow cytometry. The in vivo effect of CITCO was studied using subcutaneous (s.c.) BTSC xenograft in nude mice. RESULTS: We show for the first time that BTSCs express altered levels of nuclear receptors compared with glioma cells. The expression of CAR mRNA and protein was low in BTSCs and that increased following treatment with CITCO in culture. CITCO induced a dose-dependent decrease in growth and expansion of CD133(+) BTSCs as gliospheres in culture. Cell cycle arrest and apoptosis in BTSCs were induced by CITCO, but not in normal astrocytes. Growth of s.c BTSC xenograft in nude mice was also inhibited by CITCO. CONCLUSION: These findings indicate that CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour.

IL-7Rα confers susceptibility to experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a neurological disorder that causes paralysis in young adults and affects women more frequently than men. The etiology of MS is not known, but it is generally viewed as an autoimmune disease of the central nervous system (CNS), influenced by genetic and environmental factors. Recent studies have identified interleukin-7 receptor α (IL-7Rα) as a risk factor for MS. But the role of IL-7Rα in experimental autoimmune encephalomyelitis (EAE) model of MS is not known. In this study we demonstrate that IL-7Rα-deficient (IL-7Rα(-/-)) mice remain resistant to MOGp35-55-induced EAE. When compared with C57BL/6 wild-type mice, IL-7Rα(-/-) mice showed less severe inflammation and demyelination in the CNS. The attenuation of EAE in IL-7Rα(-/-) mice was associated with a decrease in T-helper (Th) 1 and Th17 responses in the CNS and lymphoid organs. IL-7Rα(-/-) mice also showed an increase in Th2 response and CD4(+)Foxp3(+) regulatory T cells. These findings highlight that IL-7Rα confers susceptibility by influencing autoimmune Th1/Th17 responses in EAE model of MS.

National swine flu adult assessment guidelines: retrospective validation of objective criteria in three proxy datasets.

OBJECTIVES: To validate the objective criteria in the Department of Health Adult Swine Flu Assessment Tool against proxy datasets for pandemic influenza. DESIGN: Comparative validation study with 3 datasets. SETTING: Urban Emergency Department (group 1) and prehospital care (groups 2 and 3). PARTICIPANTS: Adults with community-acquired pneumonia (group 1, n=281), shortness of breath (group 2, n=211) or any respiratory diagnosis (group 3, n=300). OUTCOME MEASURES: Hospital admission (group 1), hospital admission or intravenous therapy (group 2) and transfer to emergency department (group 3). RESULTS: Sensitivity and specificity of the tool were 0.73 (95% CI 0.67 to 0.8) and 0.83 (0.72 to 0.9) in group 1, 0.64 (0.55 to 0.71) and 0.63 (0.52 to 0.73) in group 2 and 0.84 (0.75 to 0.9) and 0.55 (0.48 to 0.62) in group 3. Analysis of individual components of the tool and a summative score is presented. CONCLUSIONS: The objective criteria of the proposed DH assessment tool do not perform particularly well in predicting relevant clinical outcomes in feasible proxy conditions for pandemic influenza.

PPARgamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells.

Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARgamma agonist, 15-Deoxy-Delta(12,14)-Prostaglandin J(2) (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARgamma in gliosphere cells. These findings demonstrate that PPARgamma agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour.

Association of age and heart rate with pulsed-wave Doppler measurements in healthy, nonsedated cats.

BACKGROUND: Associations of age and heart rate with blood flow velocities and durations assessed by pulsed-wave (PW) Doppler echocardiography in cats are incompletely understood. OBJECTIVES: To determine the effects of age and heart rate on blood flow velocities and durations of cardiac events obtained by PW Doppler echocardiography in healthy, nonsedated cats. ANIMALS: A convenience sample of 87 healthy, nonsedated cats aged 3 months to 19 years. METHODS: Prospective, observational study. PW Doppler measurements were obtained by echocardiography. Association of age and heart rate with PW Doppler values was evaluated by simple and multiple linear regressions and ANCOVA. RESULTS: Significant weak positive relationships were found between age and isovolumic relaxation time (IVRT) (R2= 0.18; P< or = .001), and between age and duration of pulmonary venous retrograde flow (R2= 0.07; P= .041). There was a significant weak negative relationship between age and transmitral peak early diastolic velocity (R2= 0.19; P< or = .001). Age and heart rate were significantly related to pulmonary venous peak systolic velocity (R2= 0.13; P= .008). Heart rate affected transmitral peak late diastolic velocity (R2= 0.11; P= .006). After adjusting for heart rate effect, the PW Doppler variables that were significantly different between age groups were transmitral peak early diastolic velocity (P< or = .001), duration of transmitral late diastolic flow (P< or = .001), IVRT (P< or = .001), and the ratio of duration of transmitral late diastolic flow to duration of pulmonary venous retrograde flow (P= .029). CONCLUSIONS AND CLINICAL IMPORTANCE: The association of several PW Doppler-derived variables and age and heart rate is weak and not clinically important.