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Background: Although they are effective in outpatient settings, computerized reminders have not been proved to increase preventive care in inpatient settings., Methods: We conducted a randomized, controlled trial to determine the effects of computerized reminders on the rates at which four preventive therapies were ordered for inpatients. During an 18-month study period, a computerized system processed on-line information for all 6371 patients admitted to a general-medicine service (for a total of 10,065 hospitalizations), generating preventive care reminders as appropriate. Physicians who were in the intervention group viewed these reminders when they were using a computerized order-entry system for inpatients., Results: The reminder system identified 3416 patients (53.6 percent) as eligible for preventive measures that had not been ordered by the admitting physician. For patients with at least one indication, computerized reminders resulted in higher adjusted ordering rates for pneumococcal vaccination (35.8 percent of the patients in the intervention group vs. 0.8 percent of those in the control group, P<0.001), influenza vaccination (51.4 percent vs. 1.0 percent, P< 0.001), prophylactic heparin (32.2 percent vs. 18.9 percent, P<0.001), and prophylactic aspirin at discharge (36.4 percent vs. 27.6 percent, P<0.001)., Conclusions: A majority of hospitalized patients in this study were eligible for preventive measures, and computerized reminders significantly increased the rate of delivery of such therapies.

A randomized, double-blind, parallel-group study comparing the efficacy and tolerability of once-daily diltiazem capsules with amlodipine tablets in patients with stable angina. After a run-in period of 1 to 3 weeks, 34 patients received once-daily diltiazem and 33 patients received amlodipine. Patients received either diltiazem, 240 mg/day, or amlodipine, 5 mg/day, for 2 weeks followed by diltiazem, 360 mg/day, or amlodipine, 10 mg/day, for 2 weeks. Standard treadmill exercise testing was the primary efficacy assessment. Patients also recorded incidence of angina attacks and use of glyceryl trinitrate spray. Both treatments gave significant improvement in time to onset of angina and time to maximal exercise. With the exception of amlodipine, 5 mg/day, both treatments gave significant increases in time to 1-mm ST segment depression. Diltiazem, 360 mg/day, gave a significant decrease in rate pressure product. There were no significant treatment differences in any of the exercise test parameters. Both treatments reduced incidence of angina attacks and use of glyceryl trinitrate spray. The incidence of edema was significantly less in patients receiving diltiazem. In conclusion, both treatments were effective in controlling patients' angina, but diltiazem was better tolerated, with a lower incidence of edema.

Radiographic images are important and expensive diagnostic tests. However, the provider caring for the patient often does not review the images directly due to time constraints. Institutions can use picture archiving and communications systems to make images more available to the provider, but this may not be the best solution. We integrated radiographic image review into the Regenstrief Medical Record System in order to address this problem. To achieve adequate performance, we store JPEG compressed images directly in the RMRS. Currently, physicians review about 5% of all radiographic studies using the RMRS image review function.

Clinicians are always searching for efficient access to clinical data. The Regenstrief Medical Record System has a printed report that fills this niche: Pocket Rounds. Handheld computers may offer an alternative, but it is unclear how effectively a handheld computer can display such data. We surveyed residents and students on the general medicine services for their opinions regarding Pocket Rounds. Those with handheld computers were given access to an electronic version of Pocket Rounds-e-Rounds. We surveyed the subjects who used e-Rounds for their opinions on the electronic format and how it compared to paper. Users overall satisfaction with Pocket Rounds was 5.8 on a seven-point scale. User s overall satisfaction for e-Rounds was 5.6 on a seven-point scale. The most useful function was retrieval of lab data for both modalities. The results suggest that the electronic format is a viable alternative to paper. Further evaluation is needed, and we plan a prospective controlled trial to study this further.

The efficient and reliable capture of vital signs and other bedside data in the non-ICU setting has been a challenging problem for the medical informatics community. The problem is compounded by the complexities associated with storage of this data into an electronic medical record system (EMRS). There are a lack of off-the-shelf solutions that satisfy the basic system requirements of bedside data capture, user authentication, data validation prior to storage, error handling, and convenience. With the current state of technology available, we feel the solution to this problem requires the presence of a PC with custom interface software at the bedside. This allows for the successful interface between available vital signs capture devices, existing EMRS s, and the user. This report summarizes the alternatives we found and our proposed solution to this important problem.

Although video-based teleconferencing is becoming more widespread in the medical profession, especially for scheduled consultations, applications for rapid assessment of acute medical problems are rare. Use of such a video system in a nursing facility may be especially beneficial, because physicians are often not immediately available to evaluate patients. We have assembled and tested a portable, wireless conferencing system to prepare for a randomized trial of the system s influence on resource utilization and satisfaction. The system includes a rolling cart with video conferencing hardware and software, a remotely controllable digital camera, light, wireless network, and battery. A semi-automated paging system informs physicians of patient s study status and indications for conferencing. Data transmission occurs wirelessly in the nursing home and then through Internet cables to the physician s home. This provides sufficient bandwidth to support quality motion images. IPsec secures communications. Despite human and technical challenges, this system is affordable and functional.

This is an experimental study on the feasibility of maintaining medical concept dictionaries in production grade relational database management systems (RDBMS.) In the past, RDBMS did not support transitive relational structures and had therefore been unsuitable for managing knowledge bases. The revised SQL-99 standard, however, may change this. In this paper we show that modern RDBMS that support recursive queries are capable of querying transitive relationships in a generic data model. We show a simple but efficient indexed representation of transitive closure. We could confirm that even challenging combined transitive relationships can be queried in SQL.

Exposure of C3HBYB/Wq hairless (hr/hr) mice to ultra-violet radiation (UVR) for 15 days induced intense tanning of their dorsal skin. Small, dark freckles appeared first, gradually enlarging and coalescing as treatment progressed yielding a uniform tan. Histologically, the gross changes in skin color were matched initially by the appearance of scattered epidermal melanocytes that subsequently proliferated to form discrete, progressively expanding and abutting populations resulting in a uniform melanocyte network throughout the basal layer of the interfollicular epidermis. In contrast, when applied topically before each daily exposure to UVR, a cream or lotion vehicle containing both vitamins C and E (Vits C/E) inhibited UVR-induced erythema and tanning. Application of Vits C/E, both before and after irradiation, was no more effective in providing photoprotection than pre-treatment only. At the tissue level, UVR-induced proliferation and melanogenesis of melanocytes were reduced compared with irradiated controls. The density of individual melanocyte populations was reduced, as was the number of melanocyte populations achieving merger (confluence) with others. Confluence grades and cell counts, estimating the maximum density of melanocyte populations in UVR-Vits C/E-treated mice, were approximately two thirds those of UVR-vehicle-treated controls. However, tanning was only one fifth that of UVR-vehicle-treated controls, suggesting that melanogenesis was also inhibited. In addition to its inhibitory actions on irradiated melanocytes, Vits C/E also inhibited UVR-induced suppression of contact hypersensitivity (CHS) in haired (Hr/hr) and hr/hr mice of the C3HBYB/Wq strain. The common denominators for most, if not all, of the influences of topically-applied Vits C/E in muting the responses of the melanocyte and immune systems to UVR may stem from the vitamins' combined ability to suppress UVR-stimulated inflammation and its associated cascade of mediators.

Even though computerized practice guidelines and workflow management (WfM) are proven effective techniques to improving quality of care and reducing costs, they are not widely deployed today. One reason for this is the impedance mismatch between guideline systems and electronic heath record (EHR) systems. This paper presents the Unified Service Action Model (USAM) that has been developed for the HL7 Reference Information Model and that conceptually integrates guidelines and workflow management into the EHR. We argue that the information items recorded in the EHR are logically similar to guideline and WfM definition. Therefore, guidelines and EHR reuse the same information structure in the USAM. This reuse is possible through a technique borrowed from natural language grammar and modal logic. The conceptual alignment of guidelines, WfM and the EHR could facilitate the sharing and deployment of guidelines in routine health care.

Guidelines have a proven ability to improve quality of health care and reduce cost, yet, guidelines are not very well deployed at the point of care. This is largely due to the impedance mismatch between decision support modules and the Electronic Medical Record (EMR.) The Unified Service Action Model (USAM) as part of the HL7's Reference Information Model provides a conceptual integration between patient data and medical knowledge. The USAM defines one action-oriented information structure for patient data, concept definitions, action plans, conditionals, and goals. This suggests a new approach to the problem of sharing data and knowledge, effectively working around the problem of missing domain terminology.

Background: An increase in the proportion of prostate carcinomas diagnosed at early, potentially curable stages has led to several changes in treatment of patients with this disease. Greater use of radical prostatectomy and external beam radiation has been documented, and recent data suggest that the use of radiation implant (brachytherapy) also has increased. Recent results from the National Cancer Data Base (NCDB) are available to explore this trend in greater detail., Methods: Data provided by 1758 hospital cancer registries for 435,264 patients diagnosed between 1992 and 1996 were studied. Reported use of brachytherapy was analyzed by year of diagnosis, region, patient age at diagnosis, and tumor grade., Results: The proportion of all prostate carcinoma patients treated with brachytherapy increased from 1.4% in 1992 to 3.0% in 1995. Ninety-six percent of brachytherapy patients were American Joint Committee on Cancer Stage I or II (with tumors classified as T1 or T2). As a proportion of patients in a stage group, the use of brachytherapy was greatest in Stage I; 3.7% of patients in this stage were treated by this modality. The increase in brachytherapy also was greatest among Stage I patients, rising from 2.0% in 1992 to 5.8% in 1996. Rates of use were greatest in the northeastern and southeastern U.S. and least frequently reported by institutions in the Midwest and the South. Brachytherapy was used across a wide range of patient age groups. Analysis by grade showed that 89.8% of patients treated with brachytherapy had well-differentiated or moderately differentiated tumors., Conclusions: Brachytherapy represented a small component of the overall pattern of care for prostate carcinoma patients in the U.S. during the interval studied. However, the rate of use of this modality for patients with localized prostate carcinoma increased substantially over the 5-year interval. This may reflect a trend toward more conservative management of prostate carcinoma. Additional monitoring and analysis of the more recent use of brachytherapy for the treatment of prostate carcinoma patients is warranted.

Skin cancer is the most frequently diagnosed cancer in the United States. Melanoma is the major cause of deaths due to skin cancer, however, squamous cell carcinoma and basal cell carcinoma account for considerable morbidity also. All three types are potentially curable if diagnosed at an early stage. Visual examination of the skin by a trained observer is a simple and effective screening tool which may be utilized in a multitude of settings. Patient education and self-examination augment the impact of office-based screening and mass screening programs.

Entrusted with the records for more than 1.5 million patients, the Regenstrief Medical Record System (RMRS) has evolved into a fast and comprehensive data repository used extensively at three hospitals on the Indiana University Medical Center campus and more than 30 Indianapolis clinics. The RMRS routinely captures laboratory results, narrative reports, orders, medications, radiology reports, registration information, nursing assessments, vital signs, EKGs and other clinical data. In this paper, we describe the RMRS data model, file structures and architecture, as well as recent necessary changes to these as we coordinate a collaborative effort among all major Indianapolis hospital systems, improving patient care by capturing city-wide laboratory and encounter data. We believe that our success represents persistent efforts to build interfaces directly to multiple independent instruments and other data collection systems, using medical standards such as HL7, LOINC, and DICOM. Inpatient and outpatient order entry systems, instruments for visit notes and on-line questionnaires that replace hardcopy forms, and intelligent use of coded data entry supplement the RMRS. Physicians happily enter orders, problems, allergies, visit notes, and discharge summaries into our locally developed Gopher order entry system, as we provide them with convenient output forms, choice lists, defaults, templates, reminders, drug interaction information, charge information, and on-line articles and textbooks. To prepare for the future, we have begun wrapping our system in Web browser technology, testing voice dictation and understanding, and employing wireless technology.

Modeling information for the electronic medical record (EMR) builds on a century of study on information and its relationship to cost and quality improvement. An initiative to examine the focus of cost and quality improvement and its relationship to information modeling resulted in the development of the Unified Service Action Model of healthcare processes, which focuses on the action as the center of cost accounting, quality accounting and privacy management. The application of this model to the HL7 Reference Information Model produced a simplification of the HL7 model at the cost of increased reliance on vocabulary terms for actions.

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis., Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined., Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months., Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes., Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

The efficacy, tolerability and 24-h duration of action of MXL capsules, a novel once-daily morphine preparation, were compared with twice-daily morphine tablets (MST Continus tablets) in patients with severe cancer pain. Eighty-five patients were recruited to this randomized, double-blind, double-dummy, crossover study. There was no significant difference between the two treatment groups in the number of occasions that escape medication was required, the pain scores at each of three time points throughout the day, and the number of nights woken due to pain. Both preparations were well tolerated with no significant difference in the number or severity of reported symptoms and side-effects. Sixteen patients withdrew from the study, of whom 13 withdrew for nontreatment-related reasons. There was no difference between the preparations in terms of expressed treatment preference. MXL capsules were shown to provide effective analgesia over the 24-h dosing interval which was comparable to that of MST Continus tablets administered twice daily.

The importance of demonstrating the effect of integrating electronic medical records into clinical practice, and methods for conducting the studies necessary to do so, are presented as a model that may be applicable to other aspects of the Integrated Advanced Information Management System (IAIMS). Integrated electronic medical record (EMR) systems offer the prospect of both improving the quality of health care by reducing variation in processes and outcomes and lowering its costs. Because such systems are expensive and require time-consuming re-engineering of health care delivery, demonstrating effectiveness should be part of system development. The expected benefits should be demonstrated using the most rigorous study design that the local clinical environment can support. Results of useful studies include both processes and outcomes of care, the latter including both objective and subjective measures. Comprehensive testing of EMR innovations requires a multispecialty team of investigators, adequate funding, and a commitment of both informaticists and clinicians. Demonstrating the beneficial effects of integrated EMR systems will facilitate their incorporation into everyday clinical care.

Background: Hospitalizations are an opportunity to provide preventive care., Objective: To determine if computer reminders, which we have shown to be effective in our ambulatory care setting, increasing the provision of inpatient preventive care., Methods: Randomized, controlled trial on the general medicine inpatient service of an urban, university-affiliated public hospital. Study subjects were 78 house staff rotating on the 6 general medicine services. The intervention was reminders to physicians printed on daily rounds reports about preventive care for which their patients were eligible, and suggested orders for preventive care provided through the physicians' workstations. The preventive care guidelines were derived from the US Preventive Care Task Force recommendations. Compliance with preventive care guidelines and house staff attitudes toward providing preventive care to hospitalized patients were the main outcome measures., Results: No significant differences were seen between intervention and control physicians in compliance with preventive care guidelines in the aggregate or when individual preventive care actions individual preventive care actions were analyzed. This was true even though most physicians endorsed providing most kinds of preventive care for hospitalized patients., Conclusions: Despite past success in increasing preventive care in the outpatient setting, we were unable, using a moderately intensive intervention, to increase the provision of preventive care during hospitalizations. The physicians providing care during the hospitalization were not the patients' primary care physicians, which proved to be an important barrier. More intensive interventions, or more direct linkages between inpatient and outpatient care providers, may be required to overcome this resistance.

Objective: To compare the antihypertensive efficacy and tolerability of a new combination preparation of diltiazem (150 mg) and hydrochlorothiazide (12.5 mg) with the individual constituents in patients with mild/moderate hypertension., Design: Multi-centre, double-blind, randomised parallel group study., Patients: Seventy-one patients with essential hypertension were recruited to the study., Treatment: Following completion of the placebo run-in period 63 patients fulfilled the prerandomisation criteria and entered the 10 week treatment period. Patients were randomised to receive either the combination preparation (D 150 mg/H 12.5 mg), diltiazem (150 mg) or hydrochlorthiazide (12.5 mg). The dosage was increased in three patients who had not attained target blood pressure (BP) control after 6 weeks., Outcome Measures: Response to treatment assessed by change from baseline in clinic and 24 h ambulatory BP., Results: The proportion of patients achieving target BP (a reduction in resting supine diastolic blood pressure (DBP) to below 90 mm Hg or a reduction of 10 mm Hg from baseline) was 80% in the combination group, 55% in the diltiazem group, and 38% in the hydrochlorothiazide group. The respective figures for reduction in supine DBP from baseline were 13.5 mm Hg, 11.2 mm Hg and 5.9 mm Hg. A similar treatment order appeared throughout each of the efficacy variables. BP control throughout the 24 h dosing interval was demonstrated by ambulatory BP monitoring. Each treatment was well tolerated., Conclusion: This study provides clear evidence of the efficacy of combination therapy with diltiazem and hydrochlorothiazide in the management of patients with hypertension.

The protein IB5 has been purified from human parotid saliva. This protein contains several repeats of a short proline-rich sequence. Dissociation constants have been measured at several discrete binding sites using 1H-NMR for the hydrolysable tannins (polyphenols) beta-1,3,6-tri-O-galloyl-D-glucopyranose, beta-1,2,4,6-tetra-O-galloyl-D-glucopyranose and beta-1,2,3,4,6-penta-O-galloyl-D-glucopyranose and the condensed proanthocyanidin (--)-epicatechin. The dissociation constants for trigalloyl glucose and pentagalloyl glucose were 15 X 10(-5) and 1.7 X 10(-5) M, respectively, which are 115 and 1660 times stronger than those previously measured under the same conditions for a single repeat of a mouse salivary proline-rich protein. The increase in affinity is ascribed to intramolecular secondary interactions, which are strengthened by the rigidity of the interacting molecules.

Robust scientific conclusions are too sparse to inform fully most of the choices that physicians must make about tests and treatments. Instead, ad hoc rules of thumb, or "heuristics," must guide them, and many of these are problematic. Physicians extrapolate from the small samples studied by clinical trials to general populations, but they do so inconsistently. Many physicians live by rules that dictate "not treating the numbers," correcting abnormalities slowly, achieving diagnostic certainty, and operating now to avoid "greater" risk in the future. Yet in each case, historical trends or statistical realities suggest either doing the opposite or investing in more discriminating heuristics. The heuristics of medicine should be discussed, criticized, refined, and then taught. More uniform use of explicit and better heuristics could lead to less practice variation and more efficient medical care.

Clinical practice guidelines are being touted as a cure for the tension between health care cost and quality. Rather than being just a means of controlling clinicians, guidelines also offer the chance to improve the quality of care by reducing practice variation and adherence to standards of good care. To be operationalized via computers, guidelines must be accepted by the clinicians, who must fully intend to follow them. They must be timely and use available data with minimal additional data entry by clinicians. Finally, they should have a measurable effect and be shown to improve care processes and/or outcomes.

Background and Design: The treatment of advanced mycosis fungoides is a therapeutic challenge. A variety of treatment approaches have been used. In our experience, chemotherapy has been most useful. The purpose of this study was to evaluate the effectiveness of the synergy previously demonstrated between methotrexate and fluorouracil in the treatment of advanced mycosis fungoides. Ten patients with mycosis fungoides and Sézary syndrome stages IIa (n = 1), II-b (n = 4), III (n = 1), IVa (n = 2), and IVb (n = 2) were treated with sequential methotrexate followed by fluorouracil and leucovorin rescue. Each patient received several courses of chemotherapy at varying intervals, as required for control of their disease., Results: The duration of treatment ranged from 3 to 78 months, with an average duration of 33 months. The number of cycles of chemotherapy administered to each patient ranged from five to 45, with an average of 18 infusions per patient. The average survival in patients with tumors was 5.25 years, with a median survival of 6 years. Eight of 10 patients achieved at least 80% clearing and the remaining two achieved at least 60% clearing. Adverse reactions were minimal and included nausea and vomiting, mucositis, and leukopenia in only one patient., Conclusion: Sequential methotrexate and fluorouracil chemotherapy is an effective and safe treatment for advanced mycosis fungoides and Sézary syndrome. This regimen is extremely well tolerated, with minimal toxic side effects.

We have extended the CARE language to facilitate interaction with providers using the Medical Gopher order entry system during patient care to create G-CARE. We have used G-CARE in several randomized controlled trials and for routine clinical applications. The language has evolved and is now able to support nearly all of the decision support. Its flexibility allows G-CARE results to be used at many points throughout the patient care process. Based on actual use of G-CARE, we have found performance issues and lack of dynamically grouped order sets are limitations which need to be addressed.

We are creating a health care information network that will link a large community medical record system to three hospital emergency departments, fifty community pharmacies, ten clinics, four health-maintenance organization (HMO) offices, and twelve homeless care sites in Indianapolis, Indiana. This project will test the feasibility of linking care providers across organizational boundaries and measure the benefits of such a network. The network will supply three kinds of information services: a "mini-medical library," patient medical record information, and a citywide prescription database incorporating a computer-based prescription-writing system. The use of medical resources, the cost of care, provider time spent giving care, and providers' opinions of the services will be used as outcomes in randomized clinical trials. Through this project, we hope to expand the information base available to the target care sites; reduce unnecessary testing and increase the efficiency of care in emergency departments; improve emergency department, office, and clinic prescribing patterns; enlarge the consortium of health care providers connected by the network; and develop strategies for successfully implementing a comprehensive city medical record resource.

Each May since 1984, the American Academy of Dermatology, using dermatologist members and American Cancer Society volunteers, has conducted a National Melanoma/Skin Cancer Prevention Program. Through free patient screenings at hospitals, community centers, and health fairs, more than 600,000 individuals have been reached. Through its educational and screening functions, this program has been considered "one of the finest examples of preventive medicine in the country" and as a model for other mass screening programs. This paper reviews some of the concepts that guide the Academy's screening program, some organizational aspects of the program, its accomplishments to date, and possible future directions.

Objective: To assess the effects on health care resource utilization of a network of microcomputer workstations for writing all inpatient orders., Design: Randomized controlled clinical trial., Setting: Inpatient internal medicine service of an urban public hospital., Subjects: A total of 5219 internal medicine patients and the 68 teams of house officers, medical students, and faculty internists who cared for them., Intervention: Microcomputer workstations, linked to a comprehensive electronic medical record system, for writing all inpatient orders., Main Outcome Measures: Total inpatient charges for each admission and charges for specific categories of orders. A time-motion study of selected interns assessed the ordering system's time consumption., Results: Intervention teams generated charges that were $887 (12.7%) lower per admission than did control teams (P = .02). Significant reductions (P < .05) were demonstrated separately for bed charges, diagnostic test charges, and drug charges. Reductions of similar proportion and statistical significance were found for hospital costs. The mean length of stay was 0.89 day shorter for intervention resident teams (P = .11). Interns in the intervention group spent an average of 33 minutes longer (5.5 minutes per patient) during a 10-hour observation period writing orders than did interns in the control group (P < .0001)., Conclusions: A network of microcomputer workstations for writing all inpatient orders significantly lowered patient charges and hospital costs. This would amount to savings of more than $3 million in charges annually for this hospital's medicine service and potentially tens of billions of dollars nationwide. However, the system required more physician time than did the paper charts. Research at other sites and system advances to reduce time requirements are warranted.

Current advances in high-speed computing and increased availability of statistical software have led to widespread use of statistical methods for the development of computerized protocols predictive of binary health outcomes. If these predictive algorithms are to be used in settings other than those for which they were developed, e.g., applied in a different geographic setting or extrapolated for use in a slightly different population, then they should be carefully validated to ensure appropriate application. Miller et al. (Stat Med. 1991) provided a comprehensive methodology for external validation of logistic prediction models, and applied these methods in a temporal validation setting. In this article, the authors emphasize how these methods can be applied to general forms of probabilistic predictions and provide several SAS macros for computation of the desired statistics.

To study the effects of computer-generated reminders for influenza vaccination of patients at high risk of pulmonary disease during the winter, we selected 4555 such patients from a population of 15,000 adults who participated in a three-year randomized trial of preventive-care reminders. The physicians who received the reminders vaccinated eligible patients twice as often as did the control physicians (P = 0.0001). There was a linear increase in the incidence of influenza in our area during the three winters under study (from 1000 to 33,451 to 71,075 cases per year), and we modeled the percentage of patients with hospitalizations, emergency room visits with chest radiography, and blood gas determinations as a logistic function of this increase. The difference in linear trends between the patients in the intervention group (whose physicians received reminders) and those in the control group was significant for emergency room visits (P less than 0.05), hospitalizations (P less than 0.01), and blood gas determinations (P less than 0.001). The most likely explanation for the difference is the greater use of influenza vaccine in the intervention group.

cDNA clones for mRNA sequences regulated by isoprenaline in mouse parotid glands were identified by differential colony hybridisation and all hybridised to a diagnostic proline-rich protein (PRP) oligonucleotide. They were divided into two cross-hybridisation groups, A and B, which were shown by hybrid-selected translations to encode acidic PRP and basic PRP, respectively. The A-type subgroup consisted of sequences homologous to the previously identified mouse PRP genes MP2 and MP3. The B-type subgroup comprised clones for the previously identified cDNA pUMP125 (MP4) as well as other PRP sequences. Six of the B-type clones contained a novel PRP cDNA (MP5) and these were sequenced. The composite MP5 cDNA was 897 nucleotides long and contained an open reading frame capable of encoding a 260-residue-long salivary PRP precursor (30% Pro, 19% Gln and 18% Gly), containing nine variant repeat units of consensus PGNQQGPPPQGGPQQ(GPP)R(PPQ). MP5 was 80% identical to the sequence of MP4 and had a high degree of similarity (60%) at its 3'-untranslated region to rat salivary glutamate/glutamine-rich protein (GRP) cDNA. Two MP5 clones contained a 273-bp intron-like insertion in the 3' untranslated region, being derived, therefore, from incompletely spliced MP5 transcripts. Northern blotting showed that, although PRP mRNA species were induced by isoprenaline, a B-type PRP mRNA was present in normal parotid glands. RNA dot-blots probed with PRP-gene-specific oligonucleotides established that MP3, MP4 and MP5 PRP mRNA were all induced by isoprenaline.

A mouse genomic B-type proline-rich protein (PRP) cosmid clone was isolated by cDNA hybridisation and mapped, the gene region was subcloned and 3770 bp were sequenced. This gene (MP4) contained three introns and encoded a 1020-nt (nt, nucleotide) mRNA for a PRP precursor 300 amino acids long arranged with 11 imperfect 18-residue proline-rich repeats. The transcriptional start point was determined by S1 nuclease mapping and primer extension to be 26 bp downstream of a TATAA sequence. Sequence comparisons revealed that only two regions from positions -650 bp - -30 bp were highly conserved in all other PRP genes, PRP boxes 1 and 2. Box 1 at positions -112 to -135 contained ets-like and rel/NFkB-like elements and was 74% conserved over 23 bp. Box 2 at positions -33 - -51 was 53% conserved over 19 bp. A search of the EMBL and GenBank sequence libraries indicated that PRP box 1 was only present upstream of the known mammalian PRP gene sequences and was absent from other genes. These conserved sequences may thus be relevant to the tissue-specific and beta-adrenergic regulation of PRP gene transcription.

Proline-rich protein (PRP) gene MP6 was isolated from a mouse BALB/c genomic DNA library in lambda EMBL3, characterised by hybridisation and restriction mapping and the promoter region, from -162 to +72 around the PRP consensus cap-site, was sequenced. In gel shift assays this region formed complexes C1 and C2 with parotid nuclear proteins which were induced by the beta-adrenergic agonist isoprenaline. DNA competition studies and direct binding assays of promoter subfragments showed that it was the sequence from -157 to -91 that was forming the isoprenaline-dependent complexes. All PRP genes conserve a 23bp. sequence, termed PRP Box1, with ets and NFkB/rel binding site-like elements, upstream of their promoters. In the MP6 promoter, PRP Box1 was within the region forming the complexes. Further gel shift assays using PRP Box1 oligonucleotides as competitors and targets indicated that the NFkB/rel binding site-like element was important in formation of the isoprenaline-inducible complexes. HeLa nuclear extracts also formed complexes with PRP Box1 similar to C1 and C2 but nuclear extracts from spleen, submandibular gland and liver did not. These complexes are thus candidate regulators for the isoprenaline-dependent and tissue-specific transcription of PRP genes.