3D Lumerical simulation of silicon photodiodes with microholes for high-speed short-reach intra-datacenter interconnects.

3D simulations are conducted using Lumerical software to study the performance of surface illuminated silicon positive-intrinsic-negative photodiodes with microholes. Drift-diffusion equations are solved including the effects of carrier lifetime due to Shockley-Read-Hall and Auger recombination mechanisms, as well as high field mobility. Lumerical's FDTD tool is used to determine the light absorption in the device. The generation profile is imported to Lumerical's CHARGE tool to determine the transient-limited impulse response. An equivalent circuit of the photodiode with microholes is developed for the simulation of an end-to-end high-speed system. Simulation results show an open eye diagram at 50 Gbps for 20µm×20µm devices.

Adjustment of publication bias using a cumulative meta-analytic framework.

OBJECTIVES: Publication bias has the potential to adversely impact clinical decision making and patient health if alternative decisions would have been made had there been complete publication of evidence. METHODS: The objective of our analysis was to determine if earlier publication of the complete evidence on rosiglitazone's risk of myocardial infarction (MI) would have changed clinical decision making at an earlier point in time. We tested several methods for adjustment of publication bias to assess the impact of potential time delays to identifying the MI effect. We then performed a cumulative meta-analysis (CMA) for both published studies (published-only data set) and all studies performed (comprehensive data set). We then created an adjusted data set using existing methods of adjustment for publication bias (Harbord regression, Peter's regression, and the nonparametric trim and fill method) applied to the limited data set. Finally, we compared the time to the decision threshold for each data set using CMA. RESULTS: Although published-only and comprehensive data sets did not provide notably different final summary estimates [OR = 1.4 (95 percent confidence interval [CI]: .95-2.05) and 1.42 (95 percent CI: 1.03-1.97)], the comprehensive data set reached the decision threshold 36 months earlier than the published-only data set. All three adjustment methods tested did not show a differential time to decision threshold versus the published-only data set. CONCLUSIONS: Complete access to studies capturing MI risk for rosiglitazone would have led to the evidence reaching a clinically meaningful decision threshold 3 years earlier.

Haemodiafiltration at increased plasma ionic strength for improved protein-bound toxin removal.

AIM: Protein-bound uraemic toxin accumulation causes uraemia-associated cardiovascular morbidity. Enhancing the plasma ionic strength releases toxins from protein binding and makes them available for removal during dialysis. This concept was implemented through high sodium concentrations ([Na+ ]) in the substituate of pre-dilution haemodiafiltration at increased plasma ionic strength (HDF-IPIS). METHODS: Ex vivo HDF-IPIS with blood tested increasing [Na+ ] to demonstrate efficacy and haemocompatibility. Haemocompatibility was further assessed in sheep using two different HDF-IPIS set-ups and [Na+ ] between 350 and 600 mmol L-1 . Safety and efficacy of para-cresyl sulphate (pCS) and indoxyl sulphate (IS) removal was further investigated in a randomized clinical pilot trial comparing HDF-IPIS to HD and HDF. RESULTS: Compared to [Na+ ] of 150 mmol L-1 , ex vivo HDF-IPIS at 500 mmol L-1 demonstrated up to 50% higher IS removal. Haemolysis in sheep was low even at [Na+ ] of 600 mmol L-1 (free Hb 0.016 ± 0.001 g dL-1 ). In patients, compared to HD, a [Na+ ] of 240 mmol L-1 in HDF-IPIS resulted in 40% greater reduction (48.7 ± 23.6 vs. 67.8 ± 7.9%; P = 0.013) in free IS. Compared to HD and HDF (23.0 ± 14.8 and 25.4 ± 10.5 mL min-1 ), the dialytic clearance of free IS was 31.6 ± 12.8 mL min-1 (P = 0.017) in HDF-IPIS, but [Na+ ] in arterial blood increased from 132 ± 2 to 136 ± 3 mmol L-1 (0 vs. 240 min; P < 0.001). CONCLUSION: HDF-IPIS is technically and clinically feasible. More effective HDF-IPIS requires higher temporary plasma [Na+ ], but dialysate [Na+ ] has to be appropriately adapted to avoid sodium accumulation.

An assessment of data quality in a multi-site electronic medical record system in Haiti.

OBJECTIVES: Strong data quality (DQ) is a precursor to strong data use. In resource limited settings, routine DQ assessment (DQA) within electronic medical record (EMR) systems can be resource-intensive using manual methods such as audit and chart review; automated queries offer an efficient alternative. This DQA focused on Haiti's national EMR - iSanté - and included longitudinal data for over 100,000 persons living with HIV (PLHIV) enrolled in HIV care and treatment services at 95 health care facilities (HCF). METHODS: This mixed-methods evaluation used a qualitative Delphi process to identify DQ priorities among local stakeholders, followed by a quantitative DQA on these priority areas. The quantitative DQA examined 13 indicators of completeness, accuracy, and timeliness of retrospective data collected from 2005 to 2013. We described levels of DQ for each indicator over time, and examined the consistency of within-HCF performance and associations between DQ and HCF and EMR system characteristics. RESULTS: Over all iSanté data, age was incomplete in <1% of cases, while height, pregnancy status, TB status, and ART eligibility were more incomplete (approximately 20-40%). Suspicious data flags were present for <3% of cases of male sex, ART dispenses, CD4 values, and visit dates, but for 26% of cases of age. Discontinuation forms were available for about half of all patients without visits for 180 or more days, and >60% of encounter forms were entered late. For most indicators, DQ tended to improve over time. DQ was highly variable across HCF, and within HCFs DQ was variable across indicators. In adjusted analyses, HCF and system factors with generally favorable and statistically significant associations with DQ were University hospital category, private sector governance, presence of local iSante server, greater HCF experience with the EMR, greater maturity of the EMR itself, and having more system users but fewer new users. In qualitative feedback, local stakeholders emphasized lack of stable power supply as a key challenge to data quality and use of the iSanté EMR. CONCLUSIONS: Variable performance on key DQ indicators across HCF suggests that excellent DQ is achievable in Haiti, but further effort is needed to systematize and routinize DQ approaches within HCFs. A dynamic, interactive "DQ dashboard" within iSanté could bring transparency and motivate improvement. While the results of the study are specific to Haiti's iSanté data system, the study's methods and thematic lessons learned holdgeneralized relevance for other large-scale EMR systems in resource-limited countries.

Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites.

AIM: As post-translational modifications of proteins may have an impact on the pathogenesis of diseases such as atherosclerosis, diabetes mellitus and chronic kidney disease (CKD), post-translational modifications are currently gaining increasing interest. In this study, a comprehensive method for analysis of these post-translational modifications is established for the clinical diagnostic routine. METHODS: Here, we analysed albumin - the most abundant plasma protein in human - isolated from patients with CKD and healthy controls by chromatographic steps and identified by MALDI mass spectrometry. Post-translational modifications of albumin were identified after digestion by analysing mass signal shifts of albumin peptides using pertinent mass databases. RESULTS: Albumin isolated from plasma of patients with CKD but not from healthy control subjects was specifically post-translationally modified by guanidinylation of lysines at positions 249, 468, 548, 565 and 588. After identification of guanidinylations as post-translational modifications of albumin isolated from patients with CKD, these modifications were quantified by mass spectrometry demonstrating a significant increase in the corresponding mass signal intensities in patients with CKD compared to healthy controls. The relative amount of guanidinylation of lysine at position 468 in patients with CKD was determined as 63 ± 32% (N = 3). Subsequently, we characterized the pathophysiological impact of the post-translational guanidinylation on the binding capacity of albumin for representative hydrophobic metabolic waste products. In vitro guanidinylation of albumin from healthy control subjects caused a decreased binding capacity of albumin in a time-dependent manner. Binding of indoxyl sulphate (protein-bound fraction) decreased from 82 ± 1% of not post-translationally modified albumin to 56 ± 1% after in vitro guanidinylation (P < 0.01), whereas the binding of tryptophan decreased from 20 to 4%. These results are in accordance with the binding of indoxyl sulphate to albumin from healthy control subjects and patients with CKD (88 ± 3 vs. 74 ± 10, P < 0.01). Thus, in vitro post-translational guanidinylation of albumin had a direct effect on the binding capacity of hydrophobic metabolites such as indoxyl sulphate and tryptophan. CONCLUSION: We used a mass spectrometry-based method for the characterization of post-translational modification and demonstrated the pathophysiological impact of a representative post-translational modification of plasma albumin. The data described in this study may help to elucidate the pathophysiological role of protein modifications.

Inclusion of patient-reported outcome measures in registered clinical trials: Evidence from ClinicalTrials.gov (2007-2013).

BACKGROUND: Patient reported outcomes (PROs) have gained a prominent place in clinical research. Previous estimates suggest that PRO measures are used in 14% of clinical trials. Online registries, such as ClinicalTrials.gov, may be useful in evaluating extent of PRO use. PURPOSE: To estimate the proportion of clinical trials using at least one PRO measure and to examine associations between trial characteristics and use of PRO measures. METHODS: A copy of the ClinicalTrials.gov database was made, containing all data from November 2007 to December 2013. Content was searched for use of PRO measures. Multivariable logistic regression was used to investigate possible associations between trial-level characteristics and use of PRO measures. RESULTS: Of 96,736 registered trials, 26,337 (27%) were identified as using one or more PRO measures. Among oncology trials, 29% (3947/13,584) were identified as using a PRO measure, compared to 27% (22,390/83,152) of non-oncology trials. A greater proportion of trials using PRO measures were more likely to be sponsored by university/research organizations (29%) or the US government (33%), compared to industry (22%); Phase III (35%); non-randomized (32%); and evaluating devices (30%), procedures (31%) or behaviors (50%), compared to drugs (24%). Fewer were FDA-regulated (23%). CONCLUSIONS: Evidence suggests that between 2007 and 2013, there has been an increase in the number of trials that use a PRO measure, particularly in oncology trials. With initiatives such as the Patient-Focused Drug Development and FDA PRO Guidance, the trend in the use of PRO measures in clinical research will likely increase further.

The association between use of a clinical decision support tool and adherence to monitoring for medication-laboratory guidelines in the ambulatory setting.

BACKGROUND: Stage 2 Meaningful Use criteria require the use of clinical decision support systems (CDSS) on high priority health conditions to improve clinical quality measures. Although CDSS hold great promise, implementation has been fraught with challenges, evidence of their impact is mixed, and the optimal method of content delivery is unknown. OBJECTIVE: The authors investigated whether implementation of a simple clinical decision support (CDS) tool was associated with improved prescriber adherence to national medication-laboratory monitoring guidelines for safety (hepatic function, renal function, myalgias/rhabdomyolysis) and intermediate outcomes for antidiabetic (Hemoglobin A(1c); HbA(1c)) and antihyperlipidemic (low density lipoprotein; LDL) medications prescribed within a diabetes registry. METHODS: This was a retrospective observational study conducted in three phases of CDS implementation (2008-2009): pre-, transition-, and post-Prescriptions evaluated were ordered from an electronic health record within a multispecialty medical group. Adherence was evaluated within and without applying guideline-imposed time constraints. RESULTS: Forty-thousand prescriptions were ordered over three timeframes. For hepatic and renal function, the proportion of prescriptions for which labs were monitored at any time increased from 52% to 65% (p<0.001); those that met time guidelines, from 14% to 21% (p<0.001). Only 6% of required labs were drawn to monitor for myalgias/rhabdomyolysis, regardless of timeframe. Over 90% of safety labs were within normal limits. The proportion of labs monitored at any time for LDL increased from 56% to 64% (p<0.001); those that met time guidelines from 11% to 17% (p<0.001). The proportion of labs monitored at any time for HbA(1c) remained the same (72%); those that met time guidelines decreased from 45% to 41% (p<0.001). CONCLUSION: A simple CDS tool may be associated with improved adherence to guidelines. Efforts are needed to confirm findings and improve the timeliness of monitoring; investigations to optimize alerts should be ongoing.

The relationship between cardiac output and dynamic cerebral autoregulation in humans.

Cerebral autoregulation adjusts cerebrovascular resistance in the face of changing perfusion pressures to maintain relatively constant flow. Results from several studies suggest that cardiac output may also play a role. We tested the hypothesis that cerebral blood flow would autoregulate independent of changes in cardiac output. Transient systemic hypotension was induced by thigh-cuff deflation in 19 healthy volunteers (7 women) in both supine and seated positions. Mean arterial pressure (Finapres), cerebral blood flow (transcranial Doppler) in the anterior (ACA) and middle cerebral artery (MCA), beat-by-beat cardiac output (echocardiography), and end-tidal Pco(2) were measured. Autoregulation was assessed using the autoregulatory index (ARI) defined by Tiecks et al. (Tiecks FP, Lam AM, Aaslid R, Newell DW. Stroke 26: 1014-1019, 1995). Cerebral autoregulation was better in the supine position in both the ACA [supine ARI: 5.0 ± 0.21 (mean ± SE), seated ARI: 3.9 ± 0.4, P = 0.01] and MCA (supine ARI: 5.0 ± 0.2, seated ARI: 3.8 ± 0.3, P = 0.004). In contrast, cardiac output responses were not different between positions and did not correlate with cerebral blood flow ARIs. In addition, women had better autoregulation in the ACA (P = 0.046), but not the MCA, despite having the same cardiac output response. These data demonstrate cardiac output does not appear to affect the dynamic cerebral autoregulatory response to sudden hypotension in healthy controls, regardless of posture. These results also highlight the importance of considering sex when studying cerebral autoregulation.

The impact of an ambulatory CPOE system on medication errors.

Few studies have evaluated the impact of an ambulatory computerized physician order entry (CPOE) system on medication errors. We conducted a retrospective analysis of 10,172 prescriptions to evaluate the impact of a basic CPOE system on prescribing-related medication errors, and found a significant decrease in the occurrence of errors.

Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal.

CONTEXT AND OBJECTIVE: Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth. PATIENTS AND METHODS: We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts. RESULTS: Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients. CONCLUSION: A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

The cost of treating ribavirin-induced anemia in hepatitis C: the impact of using recombinant human erythropoietin.

OBJECTIVE: Ribavirin-induced anemia (RIA) is a common adverse effect of chronic hepatitis C treatment. Studies have shown that the use of epoetin decreases the need for ribavirin dose reduction or discontinuation. The primary objective was to calculate the incremental cost of treating hepatitis C in those without versus with RIA, using either the strategy of ribavirin dose reduction/discontinuation or epoetin. The secondary objective was to calculate the incremental cost of using epoetin versus no epoetin to treat RIA, per ribavirin dose reduction/discontinuation averted. METHODS: Estimates from the literature and decision-analytic techniques were used to model treatment patterns and estimate the cost of managing RIA in genotype 1, 2, and 3 subjects. Sensitivity analyses were used to address uncertainty. RESULTS: Clinically significant RIA, a reduction in hemoglobin of > or = 2 g/dL (1.2 mmol/L), developed in 72% of patients in observational studies. The incremental cost of treating chronic hepatitis C decreased when employing the strategy of ribavirindose reduction/discontinuation to treat RIA, and increased by 5.7% (genotype 1) or 34.4% (genotype 2 or 3), when using epoetin. Using one-way sensitivity analyses, the cost of using epoetin per ribavirin dose reduction/discontinuation averted was $39,579-$52,023. Generalizability may be limited to settings in which a similar proportion of patients develop RIA. CONCLUSIONS: The proportional cost of treating hepatitis C when using epoetin to treat RIA is significant in genotype 2 or 3 patients. The cost of using epoetin per ribavirin dose reduction/discontinuation averted is substantial in patients with genotypes 1, 2, or 3; and varies with the probability of response to epoetin. These findings suggest that additional studies are warranted that will determine the effect of epoetin on treatment outcomes and its role as supportive therapy in patients with RIA.

Health state preference assessment in diabetic peripheral neuropathy.

OBJECTIVE: To assess patient preferences for health states associated with diabetic peripheral neuropathy (DPN). DESIGN AND INTERVENTION: Seven health states describing varying stages of disease severity in DPN were developed: mild neuropathy, painful neuropathy, severe neuropathy, minor ulcer, severe ulcer, minor amputation and major amputation. Using a computer interview, both rating scale (RS) and standard gamble (SG) preference scores were elicited from 52 patients with diabetes mellitus. SETTING: A US university medical centre and a Veterans Affairs clinic. STUDY PARTICIPANTS: Adult patients with type 1 and type 2 diabetes mellitus between the ages of 18 and 80 years. Patients were excluded if they had been diagnosed with DPN. RESULTS: Preference scores decreased in accordance with greater symptomatic and functional impairment. Median RS scores ranged from 0.89 to 0.23 for the seven health states. Median SG scores ranged from 0.96 to 0.65. CONCLUSIONS: Patient preferences for health states decrease as a function of increasing disease severity in DPN. The result is robust across the RS and SG methods of preference measurement. These results may be useful in informing policy analyses for resource allocation in patients with diabetes mellitus.

Effect of telephone follow-up on the physical well-being dimension of quality of life in patients with cancer.

OBJECTIVE: To evaluate the effect of telephone follow-up on the physical well-being dimension of health-related quality of life in patients with cancer. DESIGN: Randomized, controlled trial. SETTING: Public teaching hospital. PATIENTS: One hundred fifty patients with cancer who were discharged to home from the hospital. INTERVENTION: Patients received a telephone follow-up call 48-72 hours after discharge. Information was solicited regarding drug-related (and other) problems. Problems were addressed, and advice and support were given. MEASUREMENTS AND MAIN RESULTS: Analysis of variance revealed no differences in the physical well-being dimension of health-related quality of life between patients who received telephone follow-up and a control group who did not. Sixty-eight percent of the follow-up group and 40% of the control group (p = 0.007) reported having had at least one contact with a health professional. CONCLUSION: One possible explanation for the lack of effect of the intervention is that high-risk patients in the control group received a similar intervention from other health care professionals. We suggest that telephone follow-up be coordinated among health professionals.

Management strategies for ribavirin-induced hemolytic anemia in the treatment of hepatitis C: clinical and economic implications.

OBJECTIVES: Recently published studies have demonstrated increased efficacy and cost-effectiveness of combination therapy with interferon and alpha-2b/ribavirin compared with interferon-alpha monotherapy in the treatment of chronic hepatitis C (CHC). Combination therapy is associated with a clinically important adverse effect: ribavirin-induced hemolytic anemia (RIHA). The objective of this study was to evaluate the direct health-care costs and management of RIHA during treatment of CHC in a clinical trial setting. METHODS: A systematic literature review was conducted to synthesize information on the incidence and management of RIHA. Decision-analytic techniques were used to estimate the cost of treating RIHA. Uncertainty was evaluated using sensitivity analyses. RESULTS: RIHA, defined as a reduction in hemoglobin to less than 100 g/L, occurs in approximately 7% to 9% of patients treated with combination therapy. The standard of care for management of RIHA is reduction or discontinuation of the ribavirin dosage. We estimated the direct cost of treating clinically significant RIHA to be $170 per patient receiving combination therapy per 48-week treatment course (range $68-$692). The results of the one-way sensitivity analyses ranged from $57 to $317. In comparison, the cost of 48 weeks of combination therapy is $16,459. CONCLUSIONS: The direct cost of treating clinically significant RIHA is 1% ($170/$16,459) of drug treatment costs. Questions remain about the optimal dose of ribavirin and the incidence of RIHA in a real-world population. Despite these uncertainties, this initial evaluation of the direct cost of treating RIHA provides an estimate of the cost and management implications of this clinically important adverse effect.

A computerized system for tracking practice and prescriptive patterns of family nurse practitioner students.

Decisions about the fit between advanced practice nursing curricula and the real world of primary care practice should be based on data and not on intuition. The purpose of this article is to describe a computerized database system that can be used to: 1) track practice (including prescribing) patterns of nurse practitioner (NP) students; 2) address data issues that commonly arise; and 3) describe NP students' practice during their education to prospective employers. The database system uses both the Family Nurse Practitioners Log (FNPLOG), a faculty-developed software program, and Epi Info, a companion public domain software program. Variables are categorized as being related to sociodemographic, diagnostic, or prescriptive components of primary care. The system provides a simple, efficient, and feasible way of computerizing, analyzing, and evaluating students' clinical experience and practice patterns. The implications for advanced practice nursing education will be illustrated along with other potential uses of the database system.

Nurse practitioner student prescriptive patterns.

As employment of nurse practitioners (NPs) increases in health care systems, there is a need to have current data on their prescribing practices and patterns, and to implement a system for updating such data. This study reports prescriptive data based upon 10,421 primary care visits conducted by 55 family NP students over a 15-month period in 1997 and 1998. Numbers of over-the-counter drugs taken regularly, prescription drugs currently prescribed and prescription drugs prescribed or refilled at the visit were recorded in addition to types of drugs, compliance issues, diagnoses rendered and sociodemographic information. Individual student data were aggregated and analyzed using Epi Info (Epidemiology Program Office of the Centers for Disease Control) and SPSS-PC. Results identified that: 1) the majority of patient visits involved the prescription of 1-2 drugs (88%); 2) major compliance issues included financial concerns, knowledge deficits, and complexity/demands of treatment; 3) commonly rendered diagnoses at drug visits for chronic conditions were hypertension and diabetes; for acute conditions, otitis sinusitis and upper respiratory infections; 4) anti-microbial agents, drugs used for relief of pain, and cardiovascular drugs account for 60% of drug mentions; and 5) the numbers of drugs prescribed or refilled at visits were similar by type of preceptor, except fewer single drugs were prescribed or refilled at visits supervised by nurse preceptors. Findings are discussed relative to deepening the understanding of advanced practice nursing education and the prescribing practices of NP students and their preceptors.

Comparative evaluation of three continuous speech recognition software packages in the generation of medical reports.

OBJECTIVE: To compare out-of-box performance of three commercially available continuous speech recognition software packages: IBM ViaVoice 98 with General Medicine Vocabulary; Dragon Systems NaturallySpeaking Medical Suite, version 3.0; and L&H Voice Xpress for Medicine, General Medicine Edition, version 1.2. DESIGN: Twelve physicians completed minimal training with each software package and then dictated a medical progress note and discharge summary drawn from actual records. MEASUREMENTS: Errors in recognition of medical vocabulary, medical abbreviations, and general English vocabulary were compared across packages using a rigorous, standardized approach to scoring. RESULTS: The IBM software was found to have the lowest mean error rate for vocabulary recognition (7.0 to 9.1 percent) followed by the L&H software (13.4 to 15.1 percent) and then Dragon software (14.1 to 15.2 percent). The IBM software was found to perform better than both the Dragon and the L&H software in the recognition of general English vocabulary and medical abbreviations. CONCLUSION: This study is one of a few attempts at a robust evaluation of the performance of continuous speech recognition software. Results of this study suggest that with minimal training, the IBM software outperforms the other products in the domain of general medicine; however, results may vary with domain. Additional training is likely to improve the out-of-box performance of all three products. Although the IBM software was found to have the lowest overall error rate, successive generations of speech recognition software are likely to surpass the accuracy rates found in this investigation.

Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue.

Farnesylation of Ras is required for its transforming activity in human cancer and the reaction is catalysed by the enzyme farnesyltransferase. Recently, we discovered a novel chemical series of potent farnesyl pyrophosphate (FPP) analogues which selectively inhibited farnesyltransferase. Our most potent compound to date in this series, A-176120, selectively inhibited farnesyltransferase activity (IC(50) 1.2+/-0.3 nM) over the closely related enzymes geranylgeranyltransferase I (GGTaseI) (IC(50) 423+/-1.8 nM), geranylgeranyltransferase II (GGTaseII) (IC(50) 3000 nM) and squalene synthase (SSase) (IC(50)>10000 nM). A-176120 inhibited ras processing in H-ras-transformed NIH3T3 cells and HCT116 K-ras-mutated cells (ED(50) 1.6 and 0.5 microM, respectively). The anti-angiogenic potential of A-176120 was demonstrated by a decrease in Ras processing, cell proliferation and capillary structure formation of human umbilical vein endothelial cells (HUVEC), and a decrease in the secretion of vascular endothelial growth factor (VEGF) from HCT116 cells. In vivo, A-176120 reduced H-ras NIH3T3 tumour growth and extended the lifespan of nude mice inoculated with H- or K-ras-transformed NIH3T3 cells. A-176120 also had an additive effect in combination with cyclophosphamide in nude mice inoculated with K-ras NIH3T3 transformed cells. Overall, our results demonstrate that A-176120 is a potent FPP mimetic with both antitumour and anti-angiogenic properties.

Direct medical costs of chronic obstructive pulmonary disease: chronic bronchitis and emphysema.

In this study we aimed to estimate direct medical costs of Chronic Obstructive Pulmonary Disease (COPD) by disease type; chronic bronchitis and emphysema. This study estimates direct costs in 1996 dollars using a prevalence approach and both aggregate and microcosting. A societal perspective is taken using prevalence, and multiple national, state and local data sources are used to estimate health-care utilization and costs. Chronic bronchitis and emphysema together account for $14.5 billion in annual direct costs. Inpatient costs are greater than outpatient and emergency costs ($8.3 vs. $7.8 billion) and hospital and medication costs account for most resources spent. The high prevalence of chronic bronchitis accounts for its larger total costs ($11.7 billion) compared with emphysema ($2.8 billion). Emphysema, which is more severe, has higher costs per prevalent case ($1341 vs. $816). Hospital stays account for the highest costs, $6.0 billion for chronic bronchitis and $1.9 billion for emphysema. The hospitalization rate, length of stay and average cost per prevalent case are higher for emphysema than for chronic bronchitis. Medication costs are the second highest cost category ($4.4 billion for chronic bronchitis, $0.693 billion for emphysema). The high hospitalization and low home care costs (0.2% of total) suggest underuse of home care and room to shift from acute to preventive care. More attention to healthcare management of chronic bronchitis and emphysema is suggested, and improving inhaler and anti-smoking compliance might be important targets.

Understanding the relation between expectancies and drinking among DUI offenders using expectancy categories.

OBJECTIVE: In the context of several recent studies that have found negative expectancies to predict drinking-related variables, the present study was designed to examine the relationships among positive expectancies, negative expectancies and drinking, in a sample of DUI offenders. METHOD: Participants (N = 96; 75% male) recruited from a 3-day residential alcohol education program completed a demographic data sheet, the Negative Alcohol Expectancy Questionnaire (NAEQ), the Alcohol Expectancy Questionnaire (AEQ) and the Customary Drinking Record upon admission to treatment. At a 3-month follow-up assessment, these measures were re-administered to 49% of the sample. RESULTS: Hierarchical multiple regression revealed that both positive and negative expectancies were related to number of drinks in the previous 30 days. Stepwise multiple regression revealed that baseline drinking and negative expectancies were both related to number of drinking days at the 3-month follow-up assessment. To assess the interplay of positive and negative expectancies as they relate to drinking, participants were categorized as "low" or "high" on both the AEQ and the NAEQ. The low positive/low negative group drank more than the low positive/high negative group. There was no statistically significant difference in drinking between the high positive/low negative and the high positive/high negative group. CONCLUSIONS: This study provides additional evidence that negative alcohol expectancies are related to drinking. These findings suggest that the proposed restraining influence of negative expectancies on drinking may be reduced when a drinker has concurrent positive expectancies which are high.