Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Pneumococcal bacteremia in hospitalized Israeli adults: epidemiology and resistance to penicillin. Israeli Adult Pneumococcal Bacteremia Group.

In April 1993 a national survey of pneumococcal bacteremia in hospitalized Israeli adults was started, and this survey covered 23 of the 24 Israeli medical centers. During the first 2 years, 603 episodes of pneumococcal bacteremia were recorded. The overall annual incidence of pneumococcal bacteremia in Israeli adults was 14.5 episodes per 100,000 inhabitants, and the overall mortality rate was 27.8%. Pneumonia was the source of bacteremia in 70.8% of cases, primary bacteremia was the source in 17.5%, meningitis was the source in 7.5%, and otitis media/sinusitis was the source in 4.2%. Of the 258 pneumococcal isolates for which an MIC was determined, 88.8% were susceptible to penicillin, 9.3% were partially resistant, and only 1.9% were highly resistant. Twenty-four serogroups were identified from 398 strains tested. The highest percentage of penicillin-resistant strains belonged to serogroups 23, 19, 9, 4, and 6. Although only 13 of these 24 serogroups correspond to the serotypes included in the 23-valent pneumococcal vaccine, they accounted for 94% of all isolates.

Supporting infobuttons with terminological knowledge.

We have developed several prototype applications which integrate clinical systems with on-line information resources by using patient data to drive queries in response to user information needs. We refer to these collectively as infobuttons because they are evoked with a minimum of keyboard entry. We make use of knowledge in our terminology, the Medical Entities Dictionary (MED) to assist with the selection of appropriate queries and resources, as well as the translation of patient data to forms recognized by the resources. This paper describes the kinds of knowledge in the MED, including literal attributes, hierarchical links and other semantic links, and how this knowledge is used in system integration.

Controlled vocabulary and design of laboratory results displays.

Traditional data-review displays are driven by the ancillary systems that produced the data. A different paradigm is being used at Columbia-Presbyterian Medical Center (CPMC) where a controlled medical vocabulary-the Medical Entities Dictionary (MED) is the driving force behind laboratory data-review displays. Using hierarchical and semantic networks the authors have constructed a Web-based tool that considerably simplifies the MED-editing task required to create new displays. The tool uses knowledge in the MED to extract contextually relevant hierarchic and semantic sub-nets from the MED. The tool has a sensitivity of 92.2% and a relevance of 94.7% for retrieval of terms from the MED. Based on these results and given sufficient domains' structure within controlled vocabularies, we conclude that similar algorithms will enable applications to design and generate customized displays on-the-fly.

Empiric antibiotic treatment and the misuse of culture results and antibiotic sensitivities in patients with community-acquired bacteraemia due to urinary tract infection.

Recent data suggests that culture isolations and susceptibility profiles are overlooked, misinterpreted and are not a major determinant in the process of selecting anti-bacterial therapy. Compliance with empiric antibiotic protocols, relationship between blood culture results, change and selection of secondary antibiotic regimens and effect on outcome and length of hospitalization were assessed prospectively in 134 episodes of community-acquired bacteraemia due to urinary tract infection in adults. Empiric antibiotic protocols were correct in 112 episodes (83.6%), excessive in 12 episodes (8.95%) and inappropriate in 10 (7.5%) episodes, with no significant difference in outcome or length of hospitalization. Excluding early deaths, the adequacy of the initial antibiotic therapy was clearly associated with mortality (four deaths out of eight episodes treated incorrectly vs. 21/117 treated appropriately [P = 0.029]), but not with length of hospitalization. Antibiotic change was theoretically required in 92/119 (77.3%) episodes (27 [29.3] incorrect regimen, 65 [70.65%] excessive regimen), but actual change was made in only 43 episodes, of which three protocols were changed from a correct to an incorrect regimen, and one patient continued to receive an incorrect regimen. Eighteen out of 34 changes in excessive protocols were still excessive. Adequacy of secondary antibiotic treatment was clearly associated with outcome (5/10 vs. 4/109 [P<0.001]). Excessive protocols were not associated with better outcome or shorter hospital stay. Change of antibiotic regimen was associated with the presence of background diseases (5.6-fold increase) and inversely with hospitalization on the urology ward (0.254), but no independent factors associated with correct or incorrect secondary regimens could be identified. Although the compliance rate with empiric protocols was satisfactory, in many bacteraemic episodes blood culture results and antibiotic sensitivity profiles are overlooked, leading to higher mortality and excessive, unjustified use of expensive and broad-spectrum antibiotics. We could not identify factors associated with this disregard of susceptibility profiles.

Two rules for early prediction of bacteremia: testing in a university and a community hospital.

BACKGROUND: Two rules (model 1 and model 2) were previously derived and prospectively validated at the same institution to predict the likelihood of bacteremia. The objective of the present study was to test and compare the performance of the rules in patients admitted to two sites of inpatient care: a university hospital and a community hospital. METHODS: Clinical and laboratory data (including the variables contained in the two models) were collected within 24 hours in all patients admitted to the Department of Medicine of the Beilinson Medical Center, a university hospital in central Israel, and Emek Hospital, a community hospital in northern Israel, because of an acute infectious disease. The scores of the models were compared with the results of blood cultures. RESULTS: The percentage of bacteremia was 15% in the university and 18.5% in the community hospital. The area under the receiver-operating characteristic curve was 0.56 + or - 0.04 SE for model 1, and 0.67 + or - 0.04 SE for model 2 in the university hospital; and 0.59 + or - 0.05 SE versus 0.63 + or - 0.04 SE, respectively, in the community hospital. At the best calibration, model 1 defined low-risk groups of 205 patients in the university hospital, and 66 patients in the community hospital, with prevalences of bacteremia of 13% and 15%. The high-risk groups defined by model 1 had prevalences of 30% and 32%. Model 2 defined low-risk groups with prevalences of bacteremia of 7% (8 of 114) and 8% (6 of 76); and high-risk groups with percentages of 29% and 38%. CONCLUSIONS: The overall accuracy of the two models deteriorated significantly. Both models defined groups at high risk of bacteremia, but the percentages of bacteremia and of death in the low-risk groups do not encourage withholding blood cultures in these patients. The failure of the two models points toward the need for external validation, and for monitoring performance of prediction models over time.

Integrating DXplain into a clinical information system using the World Wide Web.

The World Wide Web(WWW) offers a cross-platform environment and standard protocols that enable integration of various applications available on the Internet. The authors use the Web to facilitate interaction between their Web-based Clinical Information System and a decision-support system-DXplain, at the Massachusetts General Hospital-using local architecture and Common Gateway Interface programs. The current application translates patients laboratory test results into DXplain's terms to generate diagnostic hypotheses. Two different access methods are utilized for this model; Hypertext Transfer Protocol (HTTP) and TCP/IP function calls. While clinical aspects cannot be evaluated as yet, the model demonstrates the potential of Web-based applications for interaction and integration and how local architecture, with a controlled vocabulary server, can further facilitate such integration. This model serves to demonstrate some of the limitations of the current WWW technology and identifies issues such as control over Web resources and their utilization and liability issues as possible obstacles for further integration.

Bacteraemia in a community and a university hospital.

Four hundred and forty-one and 1048 episodes of bacteraemia were prospectively surveyed over a period of 18 months in two hospitals, a 450 bed community hospital and a 900 bed tertiary care urban university hospital. Incidence of bacteraemia was 2.18 per 1000 hospitalization days (10.1 per 1000 admissions) in the community hospital and 2.64 per 1000 hospitalization days (12.0 per 1000 admissions (P < 0.004)) in the university hospital. Sixty six and 62% of episodes of bacteraemia were community acquired. The majority of bacteraemic episodes originated on the internal medicine wards of both hospital--46.7% and 58.7% respectively; the incidence of bacteraemia in the medical divisions of both hospitals was 23.1 and 17.5 per 1000 admissions respectively (P < 0.01). Overall mortality rates were 22% and 26.7% respectively. 39.9% and 44% of all isolates were Gram-positive pathogens. Escherichia coli was the commonest Gram-negative pathogen in both hospitals, particularly the community hospital--47.5% vs 32.8% (P < 0.005) of all Gram-negative pathogens, while Pseudomonas spp. were significantly more common in the university hospital--18.5% vs 11.8% (P < 0.02). Non-enterococcal streptococci were more common in the community hospital while enterococci were far more common at the university hospital--15.1% vs 1% of all Gram-positive pathogens (P < 0.05). Staphylococcus epidermidis was more common among the community hospital Gram-positive bacteraemias--31.1% vs 18.6% (P < 0.005). For almost all genera and species, antibiotic resistance was higher at the university hospital. Twenty nine point four per cent of Staphylococcus aureus isolates from the university hospital were methicillin resistant compared to 2.4% at the community hospital (P < 0.005). 29.4% of all Streptococcus pneumoniae isolates at the university hospital were penicillin resistant while no resistance was found at the community hospital. A high resistance rate to ofloxacin was found at the university hospital among S. aureus and Pseudomonas sp. Sources of bacteraemia did not differ significantly between the two hospitals. In conclusion, although outcome did not differ significantly for the two hospitals, there were significant differences between blood culture isolates in these two different settings. These differences may influence clinical decision-making about antibiotic therapy for patients in these hospitals.

Oral fluoroquinolone use in the community.

The use of oral fluoroquinolone in the community was evaluated in the Jezreel Valley area in northern Israel over an 8-month period. A total of 1,136 prescriptions for oral quinolones were prescribed for a population of 300,000 people. The findings of the study show that 70% of the prescriptions were initiated by outpatient clinic specialists or at hospital discharge, and that 70% of all prescriptions were justified and properly prescribed. No significant difference was found whether the initiating physician was a specialist or family practitioner or when the drug was recommended on hospital discharge. Moreover, the manner in which the different antibiotics were internally divided indicated the prescribing physicians' understanding of the properties of each drug. The results demonstrate that oral fluoroquinolones have been used in the Jezreel Valley area sparingly, judiciously, and according to each drug's properties. The high degree of justified use may reflect successful antibiotic control within the medical center serving that area.

Single-dose fosfomycin trometamol versus 5-day cephalexin regimen for treatment of uncomplicated lower urinary tract infections in women.

A randomized study was conducted to assess the clinical and microbiological efficacies of a single 3-g dose of fosfomycin trometamol for the treatment of uncomplicated lower urinary tract infections in women compared with a 5-day regimen of cephalexin at 0.5 g four times daily. One hundred twelve women, all of whom had documented infections with bacteria sensitive to both antibiotics, were included. Fifty-eight women received fosfomycin trometamol, and 54 women received cephalexin. The two groups did not differ in age, severity, or duration of current urinary tract infection, menstrual status, sexual activity, or use of contraceptives. Ninety percent of pathogens in the fosfomycin trometamol group and 81% in the cephalexin group were Escherichia coli (the difference is not significant [NS]). A clinical evaluation at the 5-day follow-up showed that 91% of the women in each group were free of symptoms, while five women in each group were considered therapy failures and were treated by another antibiotic course. A microbiological evaluation at the 5-day follow-up showed a 91% eradication rate in the fosfomycin trometamol group and an 83% eradication rate in the cephalexin group (NS). At the 1-month follow-up, a clinical evaluation demonstrated prolonged resolution in 86 and 78%, respectively, of the participating women (NS). A microbiological evaluation at 1 month demonstrated prolonged eradication in 47 (81%) women treated with fosfomycin trometamol and in 37 (68%) women treated with cephalexin (NS). Three and six women, respectively, had relapsed. No adverse reactions were reported by the fosfomycin trometamol-treated women, while three women treated with cephalexin reported mild adverse reactions but completed the study period. Fosfomycin trometamol in a single 3-g dose is as effective as a 5-day regimen of cephalexin for the treatment of uncomplicated lower urinary tract infection in women.

The use of ceftriaxone in the prevention of urinary tract infection in patients undergoing transurethral resection of the prostate (TUR-P).

We evaluated 101 patients undergoing transurethral resection of the prostate in this open randomized study in which 51 received antibiotic prophylaxis and 50 did not (control group). In those patients receiving antibiotics, ceftriaxone 1 g was administered intravenously within 1 h before transurethral prostatectomy and a second dose was given 3-4 days postoperatively, within 1 h before the suprapubic catheter was removed. The groups had similar clinical and demographic characteristics. During the 28-day study period, bacteriuria appeared in six ceftriaxone-treated patients and in 20 control patients (p < 0.005). On days 3-4 after the resection, only two patients who had received ceftriaxone had bacteriuria compared with 14 in the control group (p < 0.005). In addition, the incidence and duration of fever and length of hospitalization were shorter in the patients treated with ceftriaxone. In conclusion, these results support the use of prophylactic antibiotics in transurethral prostatectomy, even in patients at low risk of developing bacteriuria.

Group B streptococcal vertebral osteomyelitis in an adult.

Group B beta-hemolytic streptococcus (Streptococcus agalactiae) vertebral osteomyelitis was diagnosed in a 65-year-old man. The patient received a 3-week course of in-hospital intravenous ampicillin followed by ceftriaxone and continued to receive ceftriaxone therapy on an ambulatory basis for 3 more weeks. Hospitalization and follow-up were uncomplicated with no neurological sequelae. Review of the medical literature documented only 15 cases of group B streptococcal osteomyelitis in adults and only three cases of vertebral osteomyelitis due to this pathogen. As in most adult patients with group B streptococcal infections, the patient had coexisting chronic conditions (chronic obstructive lung disease, diabetes mellitus) but bacteremia was not present. Although uncommon, group B streptococcus should be considered as an opportunistic pathogen in patients with debilitating conditions, but vertebral osteomyelitis is even rarer.