The impact of new-onset cancer among veterans who are receiving warfarin for atrial fibrillation and venous thromboembolism.

BACKGROUND: A new cancer diagnosis adds significant complexity and uncertainty to the management of pre-existing warfarin therapy. OBJECTIVES: To determine how new-onset cancer affects anticoagulation control and outcomes among patients who had been receiving warfarin for atrial fibrillation (AF) compared to patients who had been receiving warfarin for venous thromboembolism (VTE) prior to cancer diagnosis. PATIENTS/METHODS: This cohort study started with 122,875 veterans who had been receiving warfarin for at least six months from a VA Medical Center between 10/1/06 and 9/30/08. We identified patients with incident cancer during this interval, and excluded those with a prior cancer history. We analyzed percent time in therapeutic range (TTR) at 6 and 12-month intervals after cancer diagnosis compared to pre-cancer baseline, as well as crude rates of warfarin-relevant outcomes (stroke, major bleeding, mortality) between patients with AF and VTE. RESULTS: Among patients with new-onset cancer, patients anticoagulated for AF outnumbered those anticoagulated for VTE more than 2.5-fold. There were no significant differences in TTR by indication for warfarin in months 0-6 or 7-12 following cancer diagnosis, but TTR decreased significantly compared to the pre-cancer baseline for both groups in months 0-6. As expected, cancer patients with VTE had significantly worse mortality at six months and one year compared to cancer patients with AF. CONCLUSION: Patients receiving chronic warfarin therapy who are newly diagnosed with cancer experience a significant decrease in TTR in the first 6months after diagnosis, regardless of indication for anticoagulation. This effect appears to attenuate in months 7-12.

Pathways to poor anticoagulation control.

BACKGROUND: While a considerable amount is known about which patient-level factors predict poor anticoagulation control with warfarin, measured by percent time in therapeutic range (TTR), less is known about predictors of time above or below target. OBJECTIVE: To identify predictors of different patterns of international normalized ratio (INR) values that account for poor control, including 'erratic' patterns, where more time is spent both above and below INR target, and unidirectional patterns, where time out of range is predominantly in one direction (low or high). METHODS: We studied 103 897 patients receiving warfarin with a target INR of 2-3 from 100 Veterans Health Administration sites between October 2006 and September 2008. Our outcomes were percent time above and below the target range. Predictors included patients' demographics, comorbidities, and other clinical data. RESULTS: Predictors of erratic patterns included alcohol abuse (5.2% more time below and 3.7% more time above, P < 0.001 for all results), taking > 16 medications (4.6% more time below and 1.8% more time above compared to taking seven or fewer medications), and four or more hospitalizations during the study (6.6% more time below and 2% more time above compared to no hospitalization). In contrast, predictors like cancer, non-alcohol drug abuse, dementia, and bipolar disorder were associated with more time below the target range (3.4%, 5.2%, 2.6%, and 3.2%, respectively) and less (or similar) time above range. CONCLUSION: Different patient-level factors predicted unidirectional below-target and 'erratic' patterns of INR control. Distinct interventions are necessary to address these two separate pathways to poor anticoagulation.

INR targets and site-level anticoagulation control: results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2-3. A patient's mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR). OBJECTIVES: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care. PATIENTS/METHODS: We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site-level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk-adjusted TTR. RESULTS: Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites' proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (P < 0.001). CONCLUSIONS: Proportion of patients with mean INR near 2.5 is a site-level 'signature' of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.

Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent.

The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contracted, ex vivo. In separate studies, FAT/CD36 translocation and FA uptake in response to muscle contractions were investigated in the perfused rat hindlimb. Exercise induced a similar increase in skeletal muscle cell surface membrane FAT/CD36 content in WT (+34%) and AMPK KD (+37%) mice. In contrast, 5-aminoimidazole-4-carboxamide ribonucleoside only induced an increase in cell surface FAT/CD36 content in WT (+29%) mice. Furthermore, in the perfused rat hindlimb, muscle contraction induced a rapid (1 min, +15%) and sustained (10 min, +24%) FAT/CD36 relocation to cell surface membranes. The increase in cell surface FAT/CD36 protein content with muscle contractions was associated with increased FA uptake, both in EDL and SOL muscle from WT and AMPK KD mice and in the perfused rat hindlimb. This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, AMPK could be important in regulation of FAT/CD36 distribution in other physiological situations.

Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: In patients receiving oral anticoagulation, improved control can reduce adverse outcomes such as stroke and major hemorrhage. However, little is known about patient-level predictors of anticoagulation control. OBJECTIVES: To identify patient-level predictors of oral anticoagulation control in the outpatient setting. PATIENTS/METHODS: We studied 124,619 patients who received oral anticoagulation from the Veterans Health Administration from October 2006 to September 2008. The outcome was anticoagulation control, summarized using percentage of time in therapeutic International Normalized Ratio range (TTR). Data were divided into inception (first 6 months of therapy; 39,447 patients) and experienced (any time thereafter; 104,505 patients). Patient-level predictors of TTR were examined by multivariable regression. RESULTS: Mean TTRs were 48% for inception management and 61% for experienced management. During inception, important predictors of TTR included hospitalizations (the expected TTR was 7.3% lower for those with two or more hospitalizations than for the non-hospitalized), receipt of more medications (16 or more medications predicted a 4.3% lower than for patients with 0-7 medications), alcohol abuse (-4.6%), cancer (-3.1%), and bipolar disorder (-2.9%). During the experienced period, important predictors of TTR included hospitalizations (four or more hospitalizations predicted 9.4% lower TTR), more medications (16 or more medications predicted 5.1% lower TTR), alcohol abuse (-5.4%), female sex (- 2.9%), cancer (-2.7%), dementia (-2.6%), non-alcohol substance abuse (-2.4%), and chronic liver disease (-2.3%). CONCLUSIONS: Some patients receiving oral anticoagulation therapy are more challenging to maintain within the therapeutic range than others. Our findings can be used to identify patients who require closer attention or innovative management strategies to maximize benefit and minimize harm from oral anticoagulation therapy.

Anticoagulation for valvular heart disease in community-based practice.

Little is known about patients who receive oral anticoagulation for valvular heart disease (VHD) in community-based practice. It was this study's objective to describe the characteristics, management, and outcomes of patients anticoagulated for VHD, compared to patients anticoagulated for atrial fibrillation (AF). We used a nationally-representative cohort of community-based anticoagulation care in the United States. Data collected included indications for therapy, demographics, selected comorbid conditions, international normalised ratio (INR) target ranges, INR control, and clinical outcomes. We identified 1,057 patients anticoagulated for VHD (15.6% of the overall cohort) and 3,396 patients anticoagulated for AF (50.2%). INR variability was similar between the two groups (0.64 vs. 0.69, p = 0.80). Among patients with aortic VHD, for whom a standard (2-3) target INR range is recommended, 461 (84%) had a high target range (2.5-3.5), while 95 (16%) had a standard target range. VHD patients had a higher rate of major haemorrhage compared to AF patients (3.57 vs. 1.78 events per 100 patient-years, incidence rate ratio 2.02, 95% CI 1.33 - 3.06). The rate of stroke/systemic embolus was similar between groups (0.67 vs. 0.97 events per 100 patient-years, incidence rate ratio 0.71, 95% CI 0.32 - 1.57). In our community-based study, approximately 15.6% of patients receiving warfarin were anticoagulated for VHD. VHD patients achieved similar anticoagulation control to patients with AF, as measured by INR variability. Nevertheless, the rate of major haemorrhage was elevated among VHD patients compared to AF patients; this finding requires further investigation.

Warfarin dose management affects INR control.

BACKGROUND: Little is known about how patterns of warfarin dose management contribute to percentage time in the therapeutic International Normalized Ratio (INR) range (TTR). OBJECTIVES: To quantify the contribution of warfarin dose management to TTR and to define an optimal dose management strategy. PATIENTS/METHODS: We enrolled 3961 patients receiving warfarin from 94 community-based clinics. We derived and validated a model for the probability of a warfarin dose change under various conditions. For each patient, we computed an observed minus expected (O - E) score, comparing the number of dose changes predicted by our model to the number of changes observed. We examined the ability of O - E scores to predict TTR, and simulated various dose management strategies in the context of our model. RESULTS: Patients were observed for a mean of 15.2 months. Patients who deviated the least from the predicted number of dose changes achieved the best INR control (mean TTR 70.1% unadjusted); patients with greater deviations had lower TTR (65.8% and 62.0% for fewer and more dose changes respectively, Bonferroni-adjusted P < 0.05/3 for both comparisons). On average, clinicians in our study changed the dose when the INR was 1.8 or lower/3.2 or higher (mean TTR: 68%); optimal management would have been to change the dose when the INR was 1.7 or lower/3.3 or higher (predicted TTR: 74%). CONCLUSIONS: Our observational study suggests that INR control could be improved considerably by changing the warfarin dose only when the INR is 1.7 or lower/3.3 or higher. This should be confirmed in a randomized trial.

Warfarin for atrial fibrillation in community-based practise.

BACKGROUND: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability. OBJECTIVE: To describe the management of patients with AF anticoagulated with warfarin in community-based practise. METHODS: We enrolled 3396 patients from 101 community-based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage. RESULTS: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person-years and 1.00 per 100 person-years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0-3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri-procedural INR values (67.0% vs. 67.4%, P = 0.73). CONCLUSIONS: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community-based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.

Effect of training in the fasted state on metabolic responses during exercise with carbohydrate intake.

Skeletal muscle gene response to exercise depends on nutritional status during and after exercise, but it is unknown whether muscle adaptations to endurance training are affected by nutritional status during training sessions. Therefore, this study investigated the effect of an endurance training program (6 wk, 3 day/wk, 1-2 h, 75% of peak Vo(2)) in moderately active males. They trained in the fasted (F; n = 10) or carbohydrate-fed state (CHO; n = 10) while receiving a standardized diet [65 percent of total energy intake (En) from carbohydrates, 20%En fat, 15%En protein]. Before and after the training period, substrate use during a 2-h exercise bout was determined. During these experimental sessions, all subjects were in a fed condition and received extra carbohydrates (1 g.kg body wt(-1) .h(-1)). Peak Vo(2) (+7%), succinate dehydrogenase activity, GLUT4, and hexokinase II content were similarly increased between F and CHO. Fatty acid binding protein (FABPm) content increased significantly in F (P = 0.007). Intramyocellular triglyceride content (IMCL) remained unchanged in both groups. After training, pre-exercise glycogen content was higher in CHO (545 +/- 19 mmol/kg dry wt; P = 0.02), but not in F (434 +/- 32 mmol/kg dry wt; P = 0.23). For a given initial glycogen content, F blunted exercise-induced glycogen breakdown when compared with CHO (P = 0.04). Neither IMCL breakdown (P = 0.23) nor fat oxidation rates during exercise were altered by training. Thus short-term training elicits similar adaptations in peak Vo(2) whether carried out in the fasted or carbohydrate-fed state. Although there was a decrease in exercise-induced glycogen breakdown and an increase in proteins involved in fat handling after fasting training, fat oxidation during exercise with carbohydrate intake was not changed.

Effect of prior exercise on glucose metabolism in trained men.

Several studies have demonstrated that oral glucose tolerance is impaired in the immediate postexercise period. A double-tracer technique was used to examine glucose kinetics during a 2-h oral glucose (75 g) tolerance test (OGTT) 30 min after exercise (Ex, 55 min at 71 +/- 2% of peak O(2) uptake) and 24 h after exercise (Rest) in endurance-trained men. The area under the plasma glucose curve was 71% greater in Ex than in Rest (P = 0.01). The higher glucose response occurred even though whole body rate of glucose disappearance was 24% higher after exercise (P = 0.04, main effect). Whole body rate of glucose appearance was 25% higher after exercise (P = 0.03, main effect). There were no differences in total (2 h) endogenous glucose appearance (R(a)E) or the magnitude of suppression of R(a)E, although R(a)E was higher from 15 to 30 min during the OGTT in Ex. However, the cumulative appearance of oral glucose was 30% higher in Ex (P = 0.03, main effect). There were no differences in glucose clearance rate or plasma insulin responses between the two conditions. These results suggest that adaptations in splanchnic tissues by prior exercise facilitate greater glucose output from the splanchnic region after glucose ingestion, resulting in a greater glycemic response and, consequently, a greater rate of whole body glucose uptake.

Children's goals and strategies in response to conflicts within a friendship.

Little is known about the skills required for friendship, as distinct from those required for peer acceptance. The present study examined whether children's goals and strategies in friendship conflict situations are predictive of their friendship adjustment, after accounting for level of peer acceptance. Fourth- and 5th-grade children (N = 696) responded to 30 hypothetical situations in which they were having a conflict with a friend. Results indicated that children's goals were highly related to their strategies and that children's goals and strategies were predictive of their real-life friendship adjustment. Pursuing the goal of revenge toward a friend was the goal or strategy most strongly associated with lacking friends and having poor-quality friendships. Gender differences were also found for each goal and strategy, with girls displaying a more prosocial goal and strategy orientation than boys.

Smoked marijuana effects on tobacco cigarette smoking behavior.

The effects of marijuana smoke exposure on several measures of tobacco cigarette smoking behavior were examined. Eight healthy adult male volunteers, who smoked both tobacco and marijuana cigarettes, participated in residential studies, lasting 10 to 15 days, designed to measure the effects of marijuana smoke exposure on a range of behavioral variables. Tobacco cigarettes were available throughout the day (9:00 A.M. until midnight). Each day was divided into a private period (9:00 A.M. to 5:00 P.M.), during which subjects were socially isolated, and a social period (5:00 P.M. to midnight), during which subjects could interact. Under blind conditions, subjects smoked placebo and active marijuana cigarettes (0%, 1.3%, 2.3%, or 2.7% delta 9-tetrahydrocannabinol) four times daily (9:45 A.M., 1:30 P.M., 5:00 P.M. and 8:30 P.M.). Each subject was exposed to both placebo and one active dose over 2- to 5-consecutive-day intervals, and dose conditions (i.e., placebo or active) alternated throughout the study. Active marijuana smoking significantly decreased the number of daily tobacco smoking bouts, increased inter-bout intervals and decreased inter-puff intervals. Marijuana decreased the number of tobacco smoking bouts by delaying the initiation of tobacco cigarette smoking immediately after marijuana smoking, whereas decreases in inter-puff intervals were unrelated to the time of marijuana smoking. No consistent interactions between marijuana effects and social or private periods (i.e., time of day) were observed.

Female rats are protected against the fructose induced mortality of copper deficiency.

Experiments were conducted in copper deficient male and female rats fed diets containing fructose or starch in order to determine whether the same type of interaction between copper status and dietary carbohydrate found in male rats also occurs in the female rat. Mortality occurred only in the male rats fed the fructose diet deficient in copper with 40% of the animals dying during the 8 week study. Only anemia, hypercholesterolemia, increased BUN, heart hypertrophy and reduced body weight were observed in these animals which could be related to their mortality. Despite the increased mortality, plasma ceruloplasmin, erythrocyte SOD and hepatic copper concentrations were reduced to a similar extent in all rats regardless of the sex of the animals or of the type of dietary carbohydrate fed. The results of the present study indicate that although direct measurements of copper status of female rats fed fructose diet deficient in copper are similar to their male counterpart, they are apparently protected from the lethal consequences of the deficiency.

Leukotriene effects upon the transgastric potential difference and pepsin secretion.

The effects of leukotrienes on gastric mucosal function in vivo, and on acid and pepsin secretion in vitro were investigated. In cats, treatment with leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) caused significant decreases in the transgastric electrical potential difference (P.D.) and significant increases in pepsin secretion, which returned toward control levels over 30-90 min. No detectable changes were observed in either acid concentration or gastric secretion volume over the entire 210 min experimental period. Leukotriene B4 (LTB4) had no effect upon any of these parameters. Treatment with LTD4 in isolated rabbit gastric glands resulted in significant increases in pepsin secretion, with no changes observed in aminopyrine accumulation (acid secretion). These results indicate that exogeneous LTC4, LTD4 and LTE4 can affect certain gastric mucosal functions.

Augmentin compared with oxytetracycline for chest infections in general practice.

Augmentin and oxytetracycline were compared in the treatment of chest infections in general practice in an investigator-blind study of 748 patients randomly allocated to 7 days' treatment with standard doses of either Augmentin or oxytetracycline. Significantly more patients treated with Augmentin had a good overall response to therapy both at day 7 (P less than 0.001) and at day 14 (P less than 0.01). The differences between treatments were less marked for individual signs and symptoms of lower respiratory tract infections, due to smaller numbers of patients with any particular symptom. Augmentin, however, was significantly more effective than oxytetracycline in the resolution of chest pain at day 7 (P less than 0.025) and cough at day 14 (P less than 0.005). Sputum purulence was also cleared more effectively by Augmentin by day 14 (P less than 0.001). Both treatments were well tolerated, with no significant difference between treatments in the small number of adverse events. Augmentin has been shown to be an effective, well tolerated treatment for chest infections, superior to oxytetracycline in efficacy and possibly in speed of resolution of clinical symptoms.

Studies on the H2-receptor antagonism of MK-208 in isolated rabbit gastric glands.

Using isolated rabbit gastric glands, the H2-receptor antagonist MK-208 was investigated with respect to its effects on [14C]aminopyrine uptake as an index of gastric acid secretion. In addition to shifting the histamine concentration-response curve to the right in a parallel fashion, the antagonism produced by MK-208 was reversible, contrary to that previously seen in the guinea pig atria. These observations suggest that the H2-receptors responsible for mediating gastric secretion in the rabbit and the chronotropic response in guinea pig atria are different.

Studies on the properties of 3-N-[3-[3-(1-piperidinomethyl)phenoxy]-propyl]amino-4-amino-1,2, 5-thiadiazole-1-oxide (L-643,441) as an H2-receptor antagonist in isolated gastric glands.

The H2-receptor blocking properties of L-643,441 were compared with ranitidine in isolated rabbit gastric glands. [14C]Aminopyrine uptake was used as the indicator of gastric acid secretion. Unlike ranitidine, inhibition by L-643,441 was time-dependent, only partially reversible, and was not surmounted by increasing doses of histamine. These and other findings are similar to those found previously in guinea pig atria, providing further evidence that at the receptor level, the mechanism of action of L-643, 441 is different from standard H2-receptor antagonists such as ranitidine.