Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment. Main Outcomes and Measures: The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty. Results: Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths. Conclusions and Relevance: Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing. Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Implementation of a Value-Driven Outcomes Program to Identify High Variability in Clinical Costs and Outcomes and Association With Reduced Cost and Improved Quality.

IMPORTANCE: Transformation of US health care from volume to value requires meaningful quantification of costs and outcomes at the level of individual patients. OBJECTIVE: To measure the association of a value-driven outcomes tool that allocates costs of care and quality measures to individual patient encounters with cost reduction and health outcome optimization. DESIGN, SETTING, AND PARTICIPANTS: Uncontrolled, pre-post, longitudinal, observational study measuring quality and outcomes relative to cost from 2012 to 2016 at University of Utah Health Care. Clinical improvement projects included total hip and knee joint replacement, hospitalist laboratory utilization, and management of sepsis. EXPOSURES: Physicians were given access to a tool with information about outcomes, costs (not charges), and variation and partnered with process improvement experts. MAIN OUTCOMES AND MEASURES: Total and component inpatient and outpatient direct costs across departments; cost variability for Medicare severity diagnosis related groups measured as coefficient of variation (CV); and care costs and composite quality indexes. RESULTS: From July 1, 2014, to June 30, 2015, there were 1.7 million total patient visits, including 34 000 inpatient discharges. Professional costs accounted for 24.3% of total costs for inpatient episodes ($114.4 million of $470.4 million) and 41.9% of total costs for outpatient visits ($231.7 million of $553.1 million). For Medicare severity diagnosis related groups with the highest total direct costs, cost variability was highest for postoperative infection (CV = 1.71) and sepsis (CV = 1.37) and among the lowest for organ transplantation (CV ≤ 0.43). For total joint replacement, a composite quality index was 54% at baseline (n = 233 encounters) and 80% 1 year into the implementation (n = 188 encounters) (absolute change, 26%; 95% CI, 18%-35%; P < .001). Compared with the baseline year, mean direct costs were 7% lower in the implementation year (95% CI, 3%-11%; P < .001) and 11% lower in the postimplementation year (95% CI, 7%-14%; P < .001). The hospitalist laboratory testing mean cost per day was $138 (median [IQR], $113 [$79-160]; n = 2034 encounters) at baseline and $123 (median [IQR], $99 [$66-147]; n = 4276 encounters) in the evaluation period (mean difference, -$15; 95% CI, -$19 to -$11; P < .001), with no significant change in mean length of stay. For a pilot sepsis intervention, the mean time to anti-infective administration following fulfillment of systemic inflammatory response syndrome criteria in patients with infection was 7.8 hours (median [IQR], 3.4 [0.8-7.8] hours; n = 29 encounters) at baseline and 3.6 hours (median [IQR], 2.2 [1.0-4.5] hours; n = 76 encounters) in the evaluation period (mean difference, -4.1 hours; 95% CI, -9.9 to -1.0 hours; P = .02). CONCLUSIONS AND RELEVANCE: Implementation of a multifaceted value-driven outcomes tool to identify high variability in costs and outcomes in a large single health care system was associated with reduced costs and improved quality for 3 selected clinical projects. There may be benefit for individual physicians to understand actual care costs (not charges) and outcomes achieved for individual patients with defined clinical conditions.

Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity.

Enoxaparin is commonly used to prevent venous thromboembolism(VTE) [1,2] but has not been well-studied in patients with extreme obesity,a population at high risk for VTE. We prospectively compared three enoxaparin dosing regimens for the achievement of goal peak anti-Factor Xa levels in medically ill patients (n 5 31) with extreme obesity (body mass index (BMI) ‡ 40 kg/m2). Patients were assigned to receive fixed-dose (FD) enoxaparin 40 mg daily (QDay, n 5 11), weight based,lower-dose (LD) enoxaparin 0.4 mg/kg QDay (n 5 9), or weight based,higher-dose (HD) enoxaparin 0.5 mg/kg QDay (n 5 11). The average BMI and weight of the entire cohort was 62.1 kg/m2 (range40.5­82.4) and 176 kg (range 115­256 kg) and did not differ between groups. Peak anti-Factor Xa levels were significantly higher in the HD group compared to either LD or FD groups. Patients in the HD group achieved target anti-Factor Xa levels more frequently than the LD and FD groups (P < 0.05). Peak anti-Factor Xa levels did not correlate with age, weight, BMI, or creatinine clearance, demonstrating the predictability of weight-based enoxaparin dosing. There were no adverse events (e.g., bleeding, thrombosis, thrombocytopenia). To our knowledge this is the first prospective comparative study demonstrating that in extremely obese, medically ill patients enoxaparin 0.5 mg/kg QDay is superior to FD and LD enoxaparin for the achievement of target anti-Factor Xa levels.

Health benefits of gastric bypass surgery after 6 years.

CONTEXT: Extreme obesity is associated with health and cardiovascular disease risks. Although gastric bypass surgery induces rapid weight loss and ameliorates many of these risks in the short term, long-term outcomes are uncertain. OBJECTIVE: To examine the association of Roux-en-Y gastric bypass (RYGB) surgery with weight loss, diabetes mellitus, and other health risks 6 years after surgery. DESIGN, SETTING, AND PARTICIPANTS: A prospective Utah-based study conducted between July 2000 and June 2011 of 1156 severely obese (body mass index [BMI] ≥ 35) participants aged 18 to 72 years (82% women; mean BMI, 45.9; 95% CI, 31.2-60.6) who sought and received RYGB surgery (n = 418), sought but did not have surgery (n = 417; control group 1), or who were randomly selected from a population-based sample not seeking weight loss surgery (n = 321; control group 2). MAIN OUTCOME MEASURES: Weight loss, diabetes, hypertension, dyslipidemia, and health-related quality of life were compared between participants having RYGB surgery and control participants using propensity score adjustment. RESULTS: Six years after surgery, patients who received RYGB surgery (with 92.6% follow-up) lost 27.7% (95% CI, 26.6%-28.9%) of their initial body weight compared with 0.2% (95% CI, -1.1% to 1.4%) gain in control group 1 and 0% (95% CI, -1.2% to 1.2%) in control group 2. Weight loss maintenance was superior in patients who received RYGB surgery, with 94% (95% CI, 92%-96%) and 76% (95% CI, 72%-81%) of patients receiving RYGB surgery maintaining at least 20% weight loss 2 and 6 years after surgery, respectively. Diabetes remission rates 6 years after surgery were 62% (95% CI, 49%-75%) in the RYGB surgery group, 8% (95% CI, 0%-16%) in control group 1, and 6% (95% CI, 0%-13%) in control group 2, with remission odds ratios (ORs) of 16.5 (95% CI, 4.7-57.6; P < .001) vs control group 1 and 21.5 (95% CI, 5.4-85.6; P < .001) vs control group 2. The incidence of diabetes throughout the course of the study was reduced after RYGB surgery (2%; 95% CI, 0%-4%; vs 17%; 95% CI, 10%-24%; OR, 0.11; 95% CI, 0.04-0.34 compared with control group 1 and 15%; 95% CI, 9%-21%; OR, 0.21; 95% CI, 0.06-0.67 compared with control group 2; both P < .001). The numbers of participants with bariatric surgery-related hospitalizations were 33 (7.9%), 13 (3.9%), and 6 (2.0%) for the RYGB surgery group and 2 control groups, respectively. CONCLUSION: Among severely obese patients, compared with nonsurgical control patients, the use of RYGB surgery was associated with higher rates of diabetes remission and lower risk of cardiovascular and other health outcomes over 6 years.

Physician alerts to prevent symptomatic venous thromboembolism in hospitalized patients.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis remains underused among hospitalized patients. We designed and carried out a large, multicenter, randomized controlled trial to test the hypothesis that an alert from a hospital staff member to the attending physician will reduce the rate of symptomatic VTE among high-risk patients not receiving prophylaxis. METHODS AND RESULTS: We enrolled patients using a validated point score system to detect hospitalized patients at high risk for symptomatic VTE who were not receiving prophylaxis. We randomized 2493 patients (82% on Medical Services) from 25 study sites to the intervention group (n=1238), in which the responsible physician was alerted by another hospital staff member, or the control group (n=1255), in which no alert was issued. The primary end point was symptomatic, objectively confirmed VTE within 90 days. Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis as control subjects (46.0% versus 20.6%; P<0.0001). The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% CI, 0.50 to 1.25), but the difference did not achieve statistical significance. The rate of major bleeding at 30 days in the alert group was similar to that in the control group (2.1% versus 2.3%; P=0.68). CONCLUSIONS: A strategy of direct notification of the physician by a staff member increases prophylaxis use and leads to a reduction in the rate of symptomatic VTE in hospitalized patients. However, VTE prophylaxis continues to be underused even after physician notification, especially among Medical Service patients.

Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study.

Warfarin remains a difficult drug to manage due to a narrow therapeutic range and wide interindividual variability in dose requirements. The relationship between warfarin sensitivity and CYP2C9 and VKORC1 variants is strong, and is the basis for several proposed dosing algorithms. Here a gene-based dosing algorithm was compared with standard of care dosing in patients receiving warfarin to prevent venous thromboembolism after joint replacement surgery. Participants (n = 229) were adults (> or =18 years) undergoing elective total hip or knee arthroplasty and receiving warfarin under the direction of a dedicated anticoagulation services team. Patients were assigned to genotype-based or standard of care dosing arms in an alternating fashion. Initial dose for patients was determined by validated algorithms from Sconce 2005 and Pendleton 2008. Management was based on INR, but dose was adjusted less aggressively for patients with CYP2C9 variants. The primary endpoint was reduction in the incidence of adverse events; additional endpoints included time to first therapeutic INR (1.8-2.9), time to first supratherapeutic INR, and percent of INR determinations that fell below, within, and above the therapeutic range. Endpoints did not achieve statistical significance, possibly due to the management of this study by a dedicated and experienced anticoagulation services team. Trends in the data suggest that patients with genetic variants progressed to a therapeutic INR faster than patients in whom genetic variants were not detected, and there were fewer adverse events in the genotype-based dosing arm. In addition, the results of this study confirm those of others demonstrating clear relationship of genotype for CYP2C9 and VKORC1 with warfarin dose requirements; as the number of variants in these genes increases, the dose requirement decreases. Of note, the gene-based algorithm utilized here significantly underpredicted the dose requirement for participants with no variants, indicating that patients with no variants should be managed with a different algorithm than patients who inherit genetic variants in CYP2C9 and/or VKORC1. In conclusion, gene-based dosing did not improve warfarin management as defined by INR dose response, using the described protocols for implementation. Findings suggest alternative strategies for dosing based on the presence or absence of genetic variants is needed.

A safe, effective, and easy to use warfarin initiation dosing nomogram for post-joint arthroplasty patients.

Venous thromboembolism (VTE) is a complication after joint arthroplasty, and pharmacologic prophylaxis is recommended to reduce this risk. Warfarin is often used, but initial dosing and management can be difficult. We studied a single-center prospective cohort of consecutive (n = 351) post-joint arthroplasty/revision patients who were initiated on warfarin using a new initiation nomogram and then discharged to home with home health services. The mean time to an international normalized ratio (INR) of 2.0 or higher was 5 days, with a mean INR of 2.1 on the fifth postoperative day. Two patients (0.6%) had an INR higher than 5 in the first 10 days of therapy. Adverse events were uncommon: 4 patients (1.14%) had VTE, 1 had major bleeding episode, and 6 patients (1.7%) had minor bleeding. A specific warfarin dosing nomogram managed by an anticoagulation service and used in joint arthroplasty/revision patients who are discharged to home with home health services leads to effective anticoagulation with few associated adverse events.

Price Transparency in Radiology-A Model for the Future.

Medicine is the only business transaction in which consumers make important purchase decisions without knowing how much they have to pay. Lack of price transparency in health care imposes financial burden and anxiety among patients as the cost of health care has been shifting from employers to patients through high-deductible health plans (HDHPs). Health economists and policymakers anticipated that HDHPs with price transparency would be a catalyst for patients to "shop" for low-price providers, thus reducing overall health care spending. For patients to shop health care services, price transparency is a requisite. The Department of Health and Human Services mandate of publicly disclosing the hospital chargemaster and state legislatures demanding greater health care price transparency are just two examples of external forces challenging the long history of price opacity in health care. Imaging, pharmacy, laboratory tests, and ambulatory surgeries are considered potentially shoppable health care services. This article examines the intended motivation of price transparency, the limitations of current price transparency tools, and what impact price transparency may have on radiology. We share our experience in developing and implementing University of Utah's online interactive price transparency tool to estimate patients' out-of-pocket expenses.

Azathioprine-induced warfarin resistance.

OBJECTIVE: To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin-azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY: A 29-year-old female with Cogan's syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient's warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION: Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966-December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin-azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75-200 mg daily. CONCLUSIONS: This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine.

The treatment of venous thromboembolism in special populations.

Anticoagulant therapy for the typical venous thromboembolism patient is straightforward with predictably favorable outcomes. However, for certain patients with venous thromboembolism, there remains uncertainty and controversy about optimal treatment. These controversial areas include venous thromboembolism patients with: heparin resistance, renal insufficiency, morbid obesity, cancer, antiphospholipid antibody syndrome, recurrent thrombosis despite appropriate anticoagulation, and patients with unprovoked VTE who may or may not benefit from thrombophilia testing. This review summarizes the current data for these special patient populations with venous thromboembolism and provides our recommendations for management.

Improving value in primary total joint arthroplasty care pathways: changes in inpatient physical therapy staffing.

BACKGROUND: An early physical therapy (PT) care pathway was implemented to provide same-day ambulation after total joint arthroplasty by changing PT staffing hours. METHODS: After receiving an exemption from our institutional review board, we performed a secondary data analysis on a cohort of patients that underwent primary TJA of the hip or knee 6 months before and 12 months after implementation of the change. Data on same-day ambulation rates, length of stay (LOS), and in-hospital costs were reviewed. RESULTS: Early evaluation and mobilization of patients by PT improved on postoperative day (POD) 0 from 64% to 85% after the change (P ≤ .001). The median LOS before the change was 3.27 days compared to 3.23 days after the change (P = .014). Patients with higher American Society of Anesthesiologists scores were less likely to ambulate on POD 0 (P = .038) and had longer hospital stays (P < .001). Early mobilization in the entire cohort was associated with a greater cost savings (P < .001). CONCLUSIONS: A relatively simple change to staffing hours, using resources currently available to us, and little additional financial or institutional investment resulted in a significant improvement in the number of patients ambulating on POD 0, with a modest reduction in both LOS and inpatient costs.

Abdominal aortitis due to Streptococcus pneumoniae and Enterobacter aerogenes: a case report and review.

Endovascular infections are 1 cause of fever of unknown origin. We describe a diagnostically challenging case of cryptogenic abdominal aortitis from Streptococcus pneumoniae and Enterobacter aerogenes. A 72-year-old male presented with epigastric pain, fevers, and chills. A computed tomography scan demonstrated enlargement and ulceration of the distal abdominal aorta, prompting urgent vascular surgery. Intraoperative tissue cultures grew S. pneumoniae and E. aerogenes and gatifloxacin was administered for 6 weeks. Spontaneous abdominal aortitis is uncommon and usually due to a single pathogen. This is the second reported case of polymicrobial infectious aortitis and to date, Enterobacter has only been reported in infected aortic grafts. Clinicians should maintain a high index of suspicion for infectious aortitis as the mortality, if only treated medically, approaches 100%.

Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism.

STUDY OBJECTIVES: To determine the incidence of heparin-induced thrombocytopenia (HIT) in patients admitted to a medical service who were given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to prevent venous thromboembolism, the incremental cost of developing HIT, and the cost consequences of using LMWH to prevent venous thromboembolism in medical patients. DESIGN: Retrospective analysis with a nested case-control. SETTING: University-affiliated tertiary-care hospital. PATIENTS: A total of 10,121 adult medical patients admitted between August 1, 2000, and November 2, 2004, received UFH or LMWH to prevent venous thromboembolism during their admission. From these, patients with immune-mediated HIT were identified and served as case patients, and 3-5 matched control patients were identified for each case patient. MEASUREMENTS AND MAIN RESULTS: The development of HIT was determined for patients who received LMWH and for patients who received UFH. Costs were compared between the patients with HIT and the matched control patients. The cost of using LMWH to prevent venous thromboembolism was compared with the cost of using UFH. In patients receiving UFH and those receiving LMWH, the incidence of HIT was 0.51% (43/8420) and 0.084% (1/1189), respectively (p=0.037), with an overall incidence of 0.43% (44/10,121). Admissions that included development of HIT incurred an average cost of 56,364 dollars compared with 15,231 dollars (p<0.001) for admissions without HIT. Using LMWH to prevent venous thromboembolism in medical patients cost 13.88 dollars less per patient than using UFH. CONCLUSIONS: For the prophylaxis of venous thromboembolism, LMWH was associated with a lower incidence of HIT than UFH in medical patients. An admission during which the patient develops HIT costs significantly more than an admission during which the patient does not develop HIT. Low-molecular-weight heparin is cost-effective for prevention of venous thromboembolism in medical patients.

A systematic approach for scale-down model development and characterization of commercial cell culture processes.

The objective of process characterization is to demonstrate robustness of manufacturing processes by understanding the relationship between key operating parameters and final performance. Technical information from the characterization study is important for subsequent process validation, and this has become a regulatory expectation in recent years. Since performing the study at the manufacturing scale is not practically feasible, development of scale-down models that represent the performance of the commercial process is essential to achieve reliable process characterization. In this study, we describe a systematic approach to develop a bioreactor scale-down model and to characterize a cell culture process for recombinant protein production in CHO cells. First, a scale-down model using 2-L bioreactors was developed on the basis of the 2000-L commercial scale process. Profiles of cell growth, productivity, product quality, culture environments (pH, DO, pCO2), and level of metabolites (glucose, glutamine, lactate, ammonia) were compared between the two scales to qualify the scale-down model. The key operating parameters were then characterized in single-parameter ranging studies and an interaction study using this scale-down model. Appropriate operation ranges and acceptance criteria for certain key parameters were determined to ensure the success of process validation and the process performance consistency. The process worst-case condition was also identified through the interaction study.

Platelet-Monocyte Aggregates and C-Reactive Protein are Associated with VTE in Older Surgical Patients.

Emerging evidence implicates platelets as key mediators of venous thromboembolism (VTE). Nevertheless, the pathways by which platelets and circulating procoagulant proteins synergistically orchestrate VTE remain incompletely understood. We prospectively determined whether activated platelets and systemic procoagulant factors were associated with VTE in 32 older orthopedic surgery patients. Circulating platelet-monocyte aggregates (PMAs), p-selectin expression (P-SEL), and integrin αIIbß3 activation (PAC-1 binding) were assessed pre-operatively and 24 hours post-operatively. The proinflammatory and procoagulant molecule C-reactive protein (CRP), which induces PMA formation in vitro, along with plasma d-dimer and fibrinogen levels were also measured. The primary outcome was VTE occurring within 30 days post-operatively. Overall, 40.6% of patients developed VTE. Patients with VTE had a significant increase in circulating PMAs and CRP post-operatively, compared to those without VTE. Changes in PMA and CRP in VTE patients were significantly correlated (r(2) = 0.536, p = 0.004). In contrast, P-SEL expression and PAC-1 binding, fibrinogen levels, and d-dimers were not associated with VTE. This is the first study to identify that increased circulating PMAs and CRP levels are early markers associated with post-surgical VTE. Our findings also provide new clinical evidence supporting the interplay between PMAs and CRP in patients with VTE.

Design and rationale of the Utah obesity study. A study to assess morbidity following gastric bypass surgery.

PURPOSE: This paper details the design and baseline characteristics of a study on the morbidity associated with Roux-en-Y gastric bypass surgery (GBP) in severely obese adults. This study is designed to assess the effectiveness of GBP in reducing morbidity and maintaining weight loss. A wide array of clinical tests and psycho-behavioral questionnaires are included as part of the study. METHODS: Three groups (n=1156 severely obese) have been recruited for this study: cases who were approved for and participated in surgery (n=415), a control group of GBP seeking individuals who were denied surgery (n=420) and a control group that was randomly chosen from a population of severely obese participants who were not seeking GBP (n=321). Clinical measures include: a physician interview and detailed medical history, resting electro- and echocardiograms, a submaximal exercise treadmill test and electrocardiogram, pulmonary function, limited polysomnography, resting metabolic rate, anthropometrics, resting and exercise blood pressure, comprehensive blood chemistry and urinalysis and dietary, quality of life and physical activity questionnaires. Most participants (76%) were tested following an overnight stay in a clinical research center. Remaining participants underwent less extensive testing in an outpatient clinic. RESULTS: Baseline characteristics of the 1156 participants are available for selected measures. Mean+/-S.D. for BMI was 46+/-7.5 kg/m(2) (range=33 to 92) and for age was 44+/-11.4 years (range=18 to 72). The prevalence of diabetes and hypertension was 19% and 35%, respectively. Of the participants who had an echocardiogram or polysomnogram, 92% had left-ventricular hypertrophy and 85% had mild to severe sleep apnea. The two control groups were similar to the surgical group. At approximately 24 months, all participants will have a second clinical examination. Statistical comparisons of changes in morbidity variables will be made between the surgical and control groups. CONCLUSIONS: This study design facilitates assessment of risks and benefits of GBP to perform recommendations on whether or not to perform surgery on the severely obese patient. Baseline and 2-year exams provide valuable data for comparison to future long-term follow-up data that can be collected at 5 and 10 years.

A developmental role for catecholamines in Drosophila behavior.

Tyrosine hydroxylase (TH), the enzyme which catalyzes the conversion of tyrosine to L-DOPA and is the rate limiting step in catecholamine biosynthesis, is genetically expressed during development in Drosophila. Null mutant alleles of the single copy gene which codes for this enzyme are developmentally lethal as is a conditional TH mutant at its restrictive temperature. In adult flies, inhibition of TH by alpha-methyl-p-tyrosine (alphaMT) decreases locomotor activity in a dose-dependent manner. This behavioral effect is accompanied by reductions in brain levels of dopamine, the primary CNS catecholamine in Drosophila, and can be prevented by the coadministration of L-DOPA. Similar effects are found with reserpine and at the restrictive temperature in flies with a temperature conditional mutation for TH. In agreement with published studies in mammals, inhibition of TH by alphaMT during Drosophila development results in enhanced expression of this enzyme in the progeny of surviving adults. This biochemical outcome is accompanied behaviorally by increased sensitivity to the locomotor effects of both alphaMT and reserpine, drugs which act via depletion of brain catecholamines. Since TH is the rate limiting enzyme responsible for the conversion of tyrosine to L-DOPA and L-DOPA is converted to dopamine by aromatic amino acid decarboxylase (AAAD), the results indicate that depletion of catecholamine levels in the fly embryo results in increased dopamine biosynthesis in the next generation accompanied by alterations in behavior.