Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

Unsaturated Cuticular Hydrocarbons Enhance Responses to Sex Pheromone in Spruce Budworm, Choristoneura fumiferana.

The primary sex pheromone components of the female spruce budworm, Choristoneura fumiferana (Clem.) (Lepidoptera: Tortricidae), are (E)- and (Z)-11-tetradecenal, produced in 95:5 ratio. However, male flight responses to calling females in a wind tunnel were faster and maintained longer than responses to any synthetic aldehyde blend. Analyses of cuticular extracts from spruce budworm adults revealed series of n-alkanes and n-monoalkenes with predominantly odd numbers of carbon atoms from C23- C29 in both sexes. (Z,Z,Z)-3,6,9-tricosatriene and (Z,Z,Z)-3,6,9-pentacosatriene were identified only in cuticular extracts from females. Pheromonally naïve males showed wing fanning and circling responses to forewing scales from females but not to scales from males. Males also exhibited the same strong responses to scales excised from pharate females, indicating that the pheromone components are produced by females prior to emergence. (Z)-11-hexadecenal and (Z)-5-tricosene enhanced male responses to the primary sex pheromone aldehydes in wind tunnel bioassays, including higher proportions of in-flight and copulatory responses by males and increased time on the source. Addition of (Z,Z,Z)-3,6,9-tricosatriene to the 95/5 blend of (E)- and (Z)-11-tetradecenal released close-range copulatory responses including abdomen curling on treated septa. We propose that the sex pheromone blend of C. fumiferana is composed of the 95/5 blend of (E)- and (Z)-11-tetradecenal as primary components, with (Z)-11-hexadecenal, (Z)-5-tricosene and (Z,Z,Z)-3,6,9-tricosatriene fulfilling secondary roles in orientation and close-range courtship.

Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs.

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

Presence of HLA antibodies in single-donor-derived fresh frozen plasma compared with pooled, solvent detergent-treated plasma (Octaplas).

Adverse reactions to plasma transfusion are well documented. One of the most serious hazards of transfusion, transfusion-related acute lung injury (TRALI), has nearly as high an incidence of mortality and major morbidity as that reported for the transfusion of incorrect blood components. The specific mechanisms of plasma component-induced adverse reactions remain unclear, but a major contribution may be related to the presence of alloantibodies. In this study, a laboratory analysis was undertaken to determine the presence of HLA antibodies in leucodepleted single-donor-derived fresh frozen plasma (FFP). A comparison was made with a pooled plasma product that has undergone solvent detergent treatment. In total, 58 plasma samples from single-donor units of leucodepleted FFP were tested along with samples from 12 units (three for each ABO blood group) of the pooled plasma (Octaplas); Octapharma Ltd, Coventry, UK), for the presence of HLA antibodies. HLA-specific enzyme-linked immunosorbent assay (ELISA) methods were used to screen for their presence, and complement-dependent cytotoxicity and flow cytometry analyses were used to further define their presence, specificity and class [immunoglobulin G (IgG)/IgM]. In the study groups, HLA antibodies were found to be present in five of the single-donor units (9%) while the pooled plasma samples tested negative.

Vesicoureteral reflux and clinical outcomes in infants with prenatally detected hydronephrosis.

PURPOSE: We evaluate the incidence of vesicoureteral reflux and urinary tract infections in infants with prenatally detected hydronephrosis. MATERIALS AND METHODS: We retrospectively reviewed the charts of children referred to our hospital for evaluation of prenatally detected hydronephrosis between 1992 and 1998. Measured variables included ultrasound and voiding cystourethrogram findings, and infectious and clinical reflux outcomes. RESULTS: Vesicoureteral reflux was identified in 40 of 234 infants (21%), including 24% of males and 13% of females. A significant correlation was found between the degree of hydronephrosis and incidence of reflux. Urinary tract infections were uncommon and identified in 7.5% of children on prevention for reflux and 4% with normal voiding cystourethrogram. In the majority (58%) of cases reflux resolved with medical management. CONCLUSIONS: The incidence of reflux increases with greater degrees of sonographic dilatation but a normal ultrasound does not exclude reflux and, therefore, voiding cystourethrogram is recommended in all children with prenatally detected hydronephrosis. Since urinary tract infections are uncommon with prevention, antibiotics should be continued until reflux resolves and/or hydronephrosis significantly improves.

Comments: implications of hormesis for industrial hygienists.

Quantitative health risk assessment is based on extrapolating from the high-dose end of the dose-response curve to points close to the origin or the threshold where the dose levels are closer to the lower environmental or occupational exposures. Hormesis is demonstrated in chronic toxicological studies where the animals treated at the lowest experimental dose appear to be healthier than the controls, as evidenced by longer life spans, less disease and/or increased body weight. If the occupational exposure limit (OEL) or environmental exposure limit (EEL) is in the range of the hormetic effect, or lower than the hormetic effect, then a case could be made that exposure at the OEL or EEL is 'safe.' This idea is controversial because it challenges some of the basic assumptions of quantitative health risk assessment as it has been practiced during the past 50 years. De-emphasis of the dose-response curve in determining OELs and EELs will occur not because of hormesis, but because the emerging sciences of genomics and proteomics will shift the focus from statistical methods to individuals as genetic and protein engineering becomes more sophisticated and powerful.

Reducing incidence of low-back injuries reduces cost.

To reduce musculoskeletal injuries in employees and to lower the financial costs associated with them, a 525-bed county nursing home in upstate New York initiated a five-step ergonomics program and purchased mechanical lifting devices. The five steps in the program were (1) creation of a resident transfer evaluation team, (2) establishment of an accident review committee, (3) mandatory ergonomics training for new nursing aides, (4) regular maintenance checks for lifting equipment, and (5) direct access to the management and budget process. During the 7-year period of this study, 8 smooth movers, 10 hydraulic stretchers, 7 Hoyer lifts, 1 Arjo lift, 9 Sarita lifts, and 1 Maxilift were purchased. Comparisons in health and financial outcomes were made between the preintervention period (1992-1993) and the intervention period (1994-1998). There was a significant reduction in the number of low-back injuries per 100 full-time nursing aides from 15.7 in the preintervention period to 11.0 in the postintervention period (p<0.05). The total number of lost workdays was significantly (p<0.05) reduced from 1476 per year before the intervention to 625 per year after the intervention. In addition, the lost workdays per full-time nursing assistant was significantly reduced from 7.8 to 3.0 (p<0.05). Although the average number of lost workdays per injury decreased from 49 to 27 days, this decrease was not statistically significant. Financially, there was a significant reduction in the average yearly cost associated with low-back injuries from $201,100 before the intervention to $91,800 during the intervention.

Anaphylactoid reactions to vitamin K.

Anaphylactoid reactions in patients receiving intravenously administered vitamin K have been reported in the literature. To summarize the known data on anaphylactoid reactions from administration of vitamin K, we reviewed all published and unpublished reports of this adverse reaction. Published reports were obtained through medline (1966--1999) and EMBASE (1971--1999) searches of the English language literature and review of references from identified case reports. Unpublished reports were obtained using the Spontaneous Reporting System Adverse Reaction database of the United States Food and Drug Administration (FDA) between August 1968 and September 1997. All adverse drug reactions to vitamin K were categorized by route of drug administration, dose and standard adverse reaction code. In the FDA reports, we defined anaphylactoid reactions as any adverse drug reaction coded as either anaphylaxis, allergic reaction, apnea, dyspnea, death, heart arrest, hypotension, shock or vasodilatation. Additionally, all fatal and life-threatening FDA reported reactions were reviewed to determine if they could represent an anaphylactoid reaction missed by the above definition. The literature review uncovered a total of 23 cases (3 fatal) of anaphylactoid reactions from intravenous vitamin K. The FDA database contained a total of 2236 adverse drug reactions reported in 1019 patients receiving vitamin K by all routes of administration. Of the 192 patients with reactions reported for intravenous vitamin K, 132 patients (69 %) had a reaction defined as anaphylactoid, with 24 fatalities (18 %) attributed to the vitamin K reaction. There were 21 patients with anaphylactoid reactions and 4 fatalities reported with doses of intravenous vitamin K of less than 5 mgs. For the 217 patients with reactions reported due to vitamin K via a non-intravenous route of administration, 38 patients had reactions meeting the definition of anaphylactoid (18 %), with 1 fatality (3 %) attributed to the drug. The absolute risk of an anaphylactoid reaction to intravenous vitamin K cannot be determined by this study, but the relatively small number of documented cases despite widespread use of this drug suggest that the reaction is rare. Anaphylactic reactions and case fatality reports were found even when intravenous vitamin K was given at low doses by slow dilute infusion. The pathogenesis of this reaction is unknown and may be multifactorial with etiologies including vasodilation induced by the solubilizing vehicle or immune-mediated processes. We conclude that use of intravenous vitamin K should be limited to patients with serious hemorrhage due to a coagulopathy that is secondary to a relative or absolute deficiency of vitamin K.

A review of the tension-free vaginal tape procedure: outcomes, complications, and theories.

In the last century, the pathophysiology of stress urinary incontinence (SUI) has been investigated and several surgical techniques have been utilized for cure. The most recent evolution in the study of SUI is the minimally invasive tension-free vaginal tape (TVT) procedure, which can be done under local anesthesia and intravenous sedation and is individualized for each patient. The procedure recreates the "hammock" of the anterior vaginal wall and endopelvic fascia with a mesh tape of polypropylene. The cure rates of the initial studies are equal to or better than other anti-incontinence procedures, and the permanent supportive mesh is very well tolerated. The TVT creates a backboard on which the urethra compresses itself when it rotates posteriorly during cough or stress. The procedure accomplishes subjective and objective cure without elevating the bladder neck or altering urethral mobility.

The Clinical Laboratory Improvement Program: not your ordinary regulatory program.

The Clinical Laboratory Improvement Amendments of 1988 (CLIA'88) established national standards of laboratory practice and test performance in the areas of registration and certification, inspection, proficiency testing, personnel qualifications, quality control, patient test management, and quality assurance. A memorandum of agreement between the Department of Health and Human Services and the Department of Defense (DOD) established the DOD Clinical Laboratory Improvement Program (CLIP) and authorized the Assistant Secretary of Defense for Health Affairs to develop CLIA'88-comparable regulations governing DOD laboratories. In implementing the DOD program, the CLIA'88 regulations were adopted to the maximum extent possible and modified only as required to meet those unique DOD missions that precluded compliance. This article provides an abbreviated historical background on CLIA'88/CLIP, defines the testing categories identified under the CLIP regulations, and briefly describes the process for application and requirements for compliance.

Automated system for capture and detection of nucleic acids.

A fully automated nucleic acid analysis system is described, which offers positive sample identification, improved sensitivity and reduced user interaction compared to conventional techniques. The system relies on the sequence-specific capture of DNA onto solid-phase particles, confirming product identity without the problems of interpretation and lack of sequence information inherent in gel-based analyses. The system can be used for sequence confirmation, mutation analysis and semiquantitative detection of PCR products.

Soil lead abatement and children's blood lead levels in an urban setting.

OBJECTIVES: The effect of abating soil lead was assessed among Baltimore children. The hypothesis was that a reduction of 1000 parts per million would reduce children's blood lead levels by 0.14 to 0.29 mumol/L (3-6 micrograms/dL). METHODS: In 2 neighborhoods (study and control), 187 children completed the protocol. In the study area, contaminated soil was replaced with clean soil. RESULTS: Soil lead abatement in this study did not lower children's blood lead. CONCLUSIONS: Although it did not show an effect in this study, soil lead abatement may be useful in certain areas.

Hiccups with high dose dexamethasone administration: a case report.

BACKGROUND: A 59-year-old male developed intractable hiccups during monthly therapy with high dose dexamethasone for multiple myeloma. Hiccups would begin hours after his first dose and continue over the 4 days of therapy. He sought assistance after his attempt at home remedies failed and the hiccups became exhausting. METHODS: The strong temporal relation between dexamethasone administration and the occurrence of hiccups indicated that dexamethasone was the cause of the patient's hiccups. Because he was responding to dexamethasone, the decision was made to continue therapy and to relieve his hiccups with metoclopramide. RESULTS: Low dose oral metoclopramide allowed the patient to continue therapy without a recurrence of the hiccups. CONCLUSIONS: Dexamethasone administration can result in intractable hiccups that persist for the duration of therapy. Low dose oral metoclopramide may prevent hiccups in patients in whom the discontinuation of dexamethasone therapy is not appropriate.

Combination Hemotherapy and Mortality Prevention (CHAMP) Study Rationale and Design.

It is now agreed that the majority of acute myocardial infarctions result from intracoronary thrombosis at sites of atherosclerotic plaque that have been disrupted. In 1947 Nicol and Fassett published the first clinical paper suggesting that agents interfering with blood coagulation could prevent myocardial infarction in patients at risk. Scores of subsequent clinical trials were performed to assess the efficacy of anticoagulants and antiplatelet agents in preventing death and reinfarction in survivors of acute myocardial infarction. Despite these efforts no agreement exists on whether these strategies are beneficial and, if so, which is superior. The primary obstacle to progress in this field has been the failure of nearly all trials to enroll the large numbers of subjects required to demonstrate a survival benefit. The large sample size requirement derives from two inescapable facts: mortality rates following acute infarction, though variable, are generally low and the potential benefit of these agents in preventing mortality is small. Combining oral anticoagulants with antiplatelet agents (combination hemotherapy) may significantly enhance their antithrombotic effect. Clinical trials of combination hemotherapy have demonstrated superiority over anticoagulant monotherapy in the setting of stroke prevention in patients with prosthetic heart valves. Similar benefit was not observed in trials studying stroke prevention in nonvalvular atrial fibrillation and vascular morbidity in patients surviving an acute myocardial infarction. The failure of these latter studies may relate to the particularly low intensity of warfarin administered in combination with aspirin. This trial proposes to demonstrate that the combination of oral anticoagulation, administered in a moderate dose intensity, and antiplatelet therapy is superior to aspirin monotherapy in reducing overall mortality following acute myocardial infarction.

Total quality improvement: an example of an effective team.

Total quality improvement (TQI) advocates that all staff members in an organization develop their own ideas on job improvement about their own specific jobs. This process helps to improve staff performance and to build continually on those improvements. This article will describe how the TQI process was used successfully by quality management staff members at a federal medical center to investigate a problem with linen.

Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report.

Within in last 7 years the literature has published several reports of acute renal failure after the administration of intravenous immunoglobulin. Review of these cases finds that all occurrences in the United States except one involved a sucrose-containing immunoglobulin preparation, leading to the suspicion that sucrose may be the cause of the renal failure. Further investigation found that approximately 50 years ago, when sucrose was used as an osmotic diuretic, investigators reported acute renal failure in humans after intravenous infusions of 50 g or more. A patient at our institution developed acute renal failure similar to that described in published case reports after being administered a sucrose-containing immunoglobulin.