'Insulin autoantibody affinity measurement using a single concentration of unlabelled insulin competitor discriminates risk in relatives of patients with type 1 diabetes.

Development of high-risk combinations of multiple islet autoantibodies and type 1 diabetes is associated with high-affinity insulin autoantibodies (IAA), but IAA affinity measurements require large serum volumes. We therefore investigated whether a simplified method of IAA affinity measurement using a low concentration of unlabelled insulin (ULI) competitor discriminated between moderate-high- and low-affinity IAA and identified individuals at highest risk of disease. Samples were assayed by radiobinding microassay using high (4·0 × 10(-5) mol/l) and low (7 × 10(-9) mol/l) ULI concentrations for competitive displacement in three cohorts of IAA-positive individuals; (1) 68 patients with newly-diagnosed type 1 diabetes; (2) 40 healthy schoolchildren; and (3) 114 relatives of patients with type 1 diabetes followed prospectively for disease development (median follow-up 13 years). IAA results obtained with low ULI were expressed as a percentage of those obtained with high ULI and this was used to classify samples as low or moderate-high affinity (0-50% and >50%, respectively). Sixty-eight patient samples were positive with high and 67 (99%) with low ULI. Forty schoolchildren were IAA-positive with high and 22 (55%) with low ULI (P < 0·001). Of the relatives, 113 were positive with high and 83 (73%) with low ULI (P < 0·001). In relatives, moderate-high affinity IAA were associated with multiple islet antibodies (P < 0·001) and greater diabetes risk than low affinity IAA (P < 0·001). A single low concentration of ULI competitor can act as a surrogate for complex IAA affinity measurements and identifies those IAA-positive relatives at highest risk of disease progression.

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia.

Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case-control WGA study in schizophrenia, examining approximately 500 000 markers, which revealed a strong effect (P=3.7 x 10(-7)) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case-control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.

Variation in institutional review board responses to a standard protocol for a multicenter clinical trial.

UNLABELLED: Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. OBJECTIVE: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. METHODS: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North AMERICA: Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. RESULTS: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40--83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26--62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. CONCLUSIONS: The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form. A national, multicenter IRB process might streamline ethical review and warrants further consideration.

Asthma education in the Emergency Department. On behalf of the MARC Investigators.

STUDY OBJECTIVE: We surveyed emergency department-based asthma researchers to study the presence of formal asthma education programs (AEPs), and examined data from prospective cohort studies to compare sites with and without AEPs. METHODS: We contacted site investigators in the Multicenter Airway Research Collaboration (MARC) in July 1998 by mail, fax, or telephone. Main outcomes were the percentage of sites using AEPs and the percentage of AEPs using each of 7 "key" teaching items in national guidelines. MARC data provided site and patient characteristics. RESULTS: All 77 site investigators (100%) responded to the survey. Using a scale from 1 to 5 (mean+/-SD), respondents identified instruction in proper inhaler technique (4.8+/-0.5), "spacer" use (4.3+/-0.7), recognition of asthma triggers (4.3+/-0.8), and rationale for medications (4. 6+/-0.6) as priorities for teaching. Twelve sites (16%; 95% confidence interval [CI] 8% to 26%) had AEPs; most (8) were at pediatric sites. Patients presenting to sites with AEPs were younger (22+/-16 years versus 25+/-15 years, P <.001), more likely to be uninsured (26% versus 23%, P <.001), and less likely to be taking inhaled corticosteroids (30% versus 37%, P <.001). AEP sites uniformly stressed "key" items, except for "written action plan" (50% of sites) and "peak flow diary" (33% of sites). CONCLUSION: Although asthma researchers agree that patient education is very important, few EDs involved in asthma research use AEPs. Sites with AEPs appear to serve patients at higher risk of poor asthma outcomes. Further study is needed to address the effectiveness of AEPs in the ED.

Recent trends and controversies in industry-sponsored clinical trials.

In recent years, industry has become an important source of funding for biomedical research. Industry-sponsored clinical trials are a particular source of controversy. In light of recent developments, the authors reevaluate the 1995 SAEM guidelines for investigator involvement in industry-sponsored clinical trials. The authors divide industry-funded clinical trials into two categories: investigator-initiated and industry-initiated, and discuss the differences between them. They examine several areas of ethical debate, including exclusivity contracts between a principal investigator and a corporate sponsor, the size of per-patient reimbursements for recruiting patients into clinical trials, and authorship criteria. Finally, the authors oppose the assumption that industry-sponsored research is automatically biased, and suggest that multiple levels of review will help to uncover bias, whatever the source. Once mutual respect for ethical guidelines and practices are established, collaboration between emergency medicine researchers and industry should be encouraged.

Utilizing national nosocomial infection surveillance system data to improve urinary tract infection rates in three intensive-care units.

OBJECTIVE: To reduce catheter-related urinary tract infection rates in three intensive-care units to at or below the National Nosocomial Infection Surveillance System pooled mean for similar units. DESIGN: A nursing team, physician team, and laboratory team reviewed and revised protocols and procedures for better catheter management. SETTING: A 500-bed community teaching hospital. INTERVENTIONS: The teams developed medical indications for urinary catheter placement and criteria that allowed the registered nurse to remove a catheter without a physician's order when no longer medically necessary. They created a computer prompt to assure a urinalysis accompanied all urine cultures. RESULTS: After introducing the new protocols, the incidence density of catheter-related urinary tract infections fell 17% in the surgical intensive-care unit, 29% in the medical intensive-care acute unit, and 45% in the coronary intensive-care acute unit. The registered nurses' compliance in removing the catheter per protocol was 88%. Physician ordering of a concomitant urinalysis with each urine culture achieved 93%. CONCLUSIONS: A multidisciplinary approach assisted in reducing catheter-associated urinary tract infections in three intensive-care units, although not to the extent desired. The teams are investigating preconnected and antimicrobial-coated catheters further.

Central venous catheter infections: concepts and controversies.

Central venous catheters (CVCs) are widely used in critically ill patients in intensive care units. However, infectious complications are common and may limit their utility. We critically review the literature to determine the impact of CVC design and composition, insertion site selection, insertion procedures, care and removal of temporary CVCs on infectious complications. Relevant articles were identified and selected for review using a database search (Medline and manual of the English language literature) based upon study design and sample size with an emphasis on prospective randomized trials. To minimize infectious complications and maintain a reasonable cost-benefit ratio, we recommend: i) use a single lumen catheter unless clear indications for a multi-lumen catheter exist; ii) insert the catheter via the subclavian vein if no relative contraindication exists (bleeding diathesis, positive pressure ventilation); iii) disinfect the insertion site employing sterile technique; iv) apply a dry, sterile dressing and change the dressing every other day; v) inspect the insertion site for signs of infection and remove the catheter if pus is present; vi) if a catheter-related infection is suspected, change the catheter over a guidewire and culture the distal segment. The replacement catheter should be removed if an original catheter segment culture is positive.

Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung injury and damage to the alveolar type II cells. This study sought to determine if endogenous surfactant is altered in ARDS. Bronchoalveolar lavage was performed in patients at-risk to develop ARDS (AR, n = 20), with ARDS (A, n = 66) and in normal subjects (N, n = 29). The crude surfactant pellet was analyzed for total phospholipids (PL), individual phospholipids, SP-A, SP-B, and minimum surface tension (STmin). PL was decreased in both AR and A (3.48 +/- 0.61 and 2.47 +/- 0.40 mumol/ml, respectively) compared to N (7.99 +/- 0.60 mumol/ml). Phosphatidylcholine was decreased in A (62.64 +/- 2.20% PL) compared to N (76.27 +/- 2.05% PL). Phosphatidylglycerol was 11.58 +/- 1.21% PL in N and was decreased to 6.48 +/- 1.43% PL in A. SP-A was 123.64 +/- 20.66 micrograms/ml in N and was decreased to 49.28 +/- 21.68 micrograms/ml in AR and to 29.88 +/- 8.49 micrograms/ml in A. SP-B was 1.28 +/- 0.33 micrograms/ml in N and was decreased to 0.57 +/- 0.24 micrograms/ml in A. STmin was increased in AR (15.1 +/- 2.53 dyn/cm) and A (29.04 +/- 2.05 dyn/cm) compared to N (7.44 +/- 1.61 dyn/cm). These data demonstrate that the chemical composition and functional activity of surfactant is altered in ARDS. Several of these alterations also occur in AR, suggesting that these abnormalities occur early in the disease process.

Yeast amber suppressors corresponding to tRNA3Leu genes.

Amber suppressors previously isolated from the yeast Saccharomyces cerevisiae and belonging to the same phenotypic class (Liebman et al., 1976) were assigned to nine different linkage groups named SUP52 through SUP60. One of these suppressors, SUP52, had been shown to cause the insertion of leucine and had been genetically mapped (Liebman et al., 1977). The following additional amber suppressors were mapped: SUP53 maps near the centromere of chromosome III closely linked to leu2; SUP54 maps on chromosome VII, 6 cM distal to trp5; SUP56 maps on chromosome I, 5.4 cM distal to ade1; SUP57 maps on chromosome VI, closely linked to met10; and SUP58 maps on the left arm of chromosome XI, loosely linked to met14. We show by protein analysis that like SUP52, the suppressors SUP53 through SUP56 are leucine-inserters. Furthermore, by hybridization with a cloned tRNA3Leu probe we demonstrate that at least SUP53, SUP54, SUP55 and SUP56 contain mutations in redundant tRNA3Leu genes because they each generate a new XbaI site in a DNA fragment encompassing a tRNA3Leu gene. These new XbaI sites are predicted by the known sequences of tRNA3Leu genes if the CAA anticodon mutates to the amber suppressing anticodon CTA. It is likely that each of the nine suppressors in this phenotypic class contain similar mutations in different tRNA3Leu genes since we find that there are approximately nine unlinked redundant copies of tRNA3Leu genes in haploid strains.

Method for determining complex operator noise exposures.

This procedure describes a field method for determining operator noise exposures that cannot be assessed from single sound level meter readings. Noise exposures that should be evaluated by this method are those characterized by time-varying operator position sound levels--sound levels that change by three decibels or more while the meter is being read. The method is based on statistical concepts and requires multiple readings for a sample period whose length is prescribed by the desired precision of the results. This new procedure compares well with the theoretical accuracy of the best dosimeters. The actual performance of the new method has been shown to be better than the actual performance of the dosimeters.