Debating clinical utility.

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.

A common intracellular allosteric binding site for antagonists of the CXCR2 receptor.

BACKGROUND AND PURPOSE: We have previously shown that SB265610 (1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea) behaves as an allosteric, inverse agonist at the C-X-C chemokine (CXCR)2 receptor. The aim of this study was to determine whether SB265610, in addition to two other known antagonists, bind to either of the two putative, topographically distinct, allosteric binding sites previously reported in the Literature. EXPERIMENTAL APPROACH: Ten single point mutations were introduced into the CXCR2 receptor using site-directed mutagenesis. Three CXCR2 antagonists were investigated, SB265610, Pteridone-1 (2-(2,3 difluoro-benzylsulphanyl)-4-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pteridin-7-one) and Sch527123 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1enylamino}-benzamide), and the effect of these mutations on their binding affinity and ability to inhibit interleukin-8-stimulated binding of [(35)S]GTPgammaS was examined. KEY RESULTS: Seven of the nine mutations introduced into the C-terminal domain and intracellular loops of the receptor produced a significant reduction in affinity at least one of the antagonists tested. Of those seven mutations, three produced a significant reduction in the affinity of all three antagonists, namely K320A, Y314A and D84N. In all but one mutation, the changes observed on antagonist affinity were matched with effects on inhibition of interleukin-8-stimulated [(35)S]GTPgammaS binding. CONCLUSIONS AND IMPLICATIONS: These antagonists bind to a common intracellular, allosteric, binding site of the CXCR2 receptor, which has been further delineated. As many of these mutations are close to the site of G protein coupling or to a region of the receptor that is responsible for the transduction of the activation signal, our results suggest a molecular mechanism for the inhibition of receptor activation.

Respiratory failure associated with the lipodystrophy syndrome in an HIV-positive patient with compromised lung function.

Protease inhibitors, used as treatment in human immunodeficiency virus (HIV) infection, are associated with a syndrome of peripheral lipodystrophy, central adiposity, hyperlipidemia and insulin resistance. An HIV-positive patient with chronic obstructive pulmonary disease is presented who developed the lipodystrophy syndrome that is associated with the use of protease inhibitors. It is postulated that the lipodystrophy syndrome further compromised his lung function, leading to respiratory failure. Patients who have pulmonary disease and are taking protease inhibitors require monitoring of clinical status and pulmonary function tests.

Clinical and microbiological follow-up of an outbreak of Yersinia pseudotuberculosis serotype Ib.

Yersinia pseudotuberculosis, a food-borne pathogen, causes infection that commonly presents as gastroenteritis and mesenteric lymphadenitis. Post-infectious complications include erythema nodosum, reactive arthritis and, less commonly, uveitis and nephritis. Six serotypes of Y. pseudotuberculosis have been identified, and post-infectious complications have been identified following infection with some, but not all, serotypes. The first recognized outbreak of Y. pseudotuberculosis serotype lb occurred in British Columbia in November 1998. We documented the incidence of post-infectious complications and the effect of antibiotic use on the clinical course. Four months after the outbreak, a standardized questionnaire asking about symptoms and antibiotic use was administered by telephone to laboratory-confirmed cases. Stool samples were collected to examine for chronic carriage of Y. pseudotuberculosis and 59 of 74 eligible cases participated. The most common post-infectious symptoms were rash (8/59) and joint pain (7/59). Microbiological analysis, at follow-up, revealed 0/36 stools positive for Y. pseudotuberculosis. Seventy-eight percent of cases had taken antibiotics during their acute illness. There was no significant difference in the frequency of post-infectious symptoms between cases who had or had not taken antibiotics. The post-infectious pathogenicity of Y. pseudotuberculosis serotype lb is lower than that documented for other serotypes. Antibiotic use did not significantly alter the reported clinical course of illness.

Misleading presentation of breast cancer in popular magazines.

CONTEXT: Women commonly misunderstand their risk for breast cancer, overestimating both their risk for developing the disease at a young age and their lifetime risk. OBJECTIVE: To determine whether age bias occurs in popular media coverage of breast cancer. SELECTION STRATEGY: The search term breast cancer was used to identify 389 articles in U.S. magazines with a circulation of at least 500,000 published between January 1, 1993, and June 30, 1997. MAIN OUTCOME MEASURES: Presence of age-related themes and age of patients with breast cancer who were described in vignettes. RESULTS: Age-related themes included breast cancer as a cause of premature death, breast cancer in mothers of young children, and the impact of a breast cancer diagnosis on dating and marriage. Factual information about age as a risk factor for breast cancer was presented in only 14% of articles, and age was often included in vignettes describing a woman with breast cancer. Thirty-four percent of the articles included one or more breast cancer vignettes. These articles included 172 unique vignettes in which patient age was described. In 84% of the vignettes (144 of 172), women were diagnosed with breast cancer before 50 years of age; in 47% (80 of 172), women were diagnosed before 40 years of age. On the basis of the age-specific incidence of breast cancer in the United States, the expected percentages would be 16% and 3.6%, respectively. CONCLUSIONS: Stories about breast cancer in popular U.S. magazines misrepresent the age distribution of the disease, emphasizing atypical cases of early-onset breast cancer and their social consequences. This presentation of breast cancer may contribute to women's fears of breast cancer and to overestimates of personal risk.

Screening for sexually transmitted diseases in human immunodeficiency virus-positive patients in Peru reveals an absence of Chlamydia trachomatis and identifies Trichomonas vaginalis in pharyngeal specimens.

To determine the prevalence of sexually transmitted diseases (STDs), we screened 107 human immunodeficiency virus-positive patients in Peru, where the virus is predominantly sexually transmitted. Patients had multiple risk factors for STDs, and 38% of women and 50% of men had at least 1 STD (gonorrhea, trichomoniasis, herpes simplex, anogenital warts, or syphilis seropositivity). No chlamydial infection was detected, even though infection rates in the general population are 5%-12%. Patients receiving trimethoprim-sulfamethoxazole(TMP-SMZ) for prophylaxis or treatment of respiratory infections were least likely to have cervicitis and/or urethritis (odds ratio, 0.37; 95% confidence interval, 0.15-0.89). Although not optimal treatment, administration of TMP-SMZ is effective against chlamydial infection. We speculate that the use of concomitant medications, such as TMP-SMZ, may be inadvertently preventing chlamydial infection in this population. Another finding was the presence of Trichomonas vaginalis in pharyngeal specimens of 3 men with histories of orogenital activity. This has not been previously reported and requires further study.

Women's interest in genetic testing for breast cancer susceptibility may be based on unrealistic expectations.

We report on results of an interview study assessing women's attitudes toward and hypothetical interest in genetic susceptibility testing for breast cancer. Data are from 246 interviews with women of varying ethnicity (African American, European American, Native American, and Ashkenazi Jewish), family history of breast cancer (negative, positive, and borderline), and educational level. Semistructured interviews included questions on general health beliefs; attitudes, experiences, and concerns about breast cancer; and hypothetical interest in genetic testing. Influence of specific test characteristics was assessed with 14 Likert scales varying negative and positive predictive value, timing of disease, possible medical interventions following a positive result. Results reported include both statistical and qualitative analysis. We found that women had a high level of interest in testing which, in general, did not vary by ethnicity, level of education, or family history. Interest in testing appeared to be shaped by an exaggerated sense of vulnerability to breast cancer, limited knowledge about genetic susceptibility testing, and generally positive views about information provided through medical screening. However, study participants were most interested in a test that didn't exist (high positive predictive value followed by effective, noninvasive, preventive therapy) and least interested in the test that does exist (less than certain positive predictive value, low negative predictive value, and limited, invasive, and objectionable therapeutic options). Our data suggest that without a careful counseling process, women could easily be motivated toward interest in a test which will not lead to the disease prevention they are seeking.

Categorizing genetic tests to identify their ethical, legal, and social implications.

Practice standards in medical genetics provide an implicit guide to the ethical, legal, and social implications (ELSI) of genetic tests. The common use of nondirective counseling reflects the principle that many testing decisions should be determined by personal values. Yet geneticists make test recommendations in some circumstances, e.g., RET mutation testing for MEN2 and newborn screening for phenylketonuria (PKU). Conversely, many geneticists recommend against testing for Apolipoprotein E (ApoE) alleles to predict Alzheimer disease (AD) risk. Taken together, these examples suggest that genetic tests can be categorized by a joint consideration of clinical validity and availability of effective treatment for persons who test positive. For genetic tests with high clinical validity/no treatment (e.g., presymptomatic testing for Huntington disease), the predominant concern is adequate nondirective counseling to ensure an informed, autonomous decision. By contrast, the predominant concern for tests with high clinical validity/effective treatment (e.g., PKU) is assuring access to care for eligible persons. For tests with limited clinical validity/no treatment (e.g., ApoE), recommending against test use can be justified on the principle of avoiding harm. For a fourth category, tests with limited clinical validity/effective treatment (e.g., HFE mutation testing for hereditary hemochromatosis), net benefit is the issue: the balance between potential benefits of treatment and potential harms of genetic labeling must be weighed. Where uncertainty exists concerning both clinical validity and effectiveness of treatment, as in the case of BRCA 1/2 mutation testing, the value of testing may vary according to different testing contexts. This approach to test categorization allows a rapid determination of the predominant ELSI concerns for different kinds of genetic tests and identifies the data most urgently needed for test evaluation.

Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 1.

Based on X-ray crystal structure information, mono charged phosphinate isosteres of phosphotyrosine have been designed and incorporated in a short inhibitory peptide sequence of the Grb2-SH2 domain. The resulting compounds, by exploiting additional interactions, inhibit binding to the Grb2-SH2 domain as potently as the corresponding doubly charged (phosphonomethyl)phenylalanine analogue.

Structure-based design and synthesis of phosphinate isosteres of phosphotyrosine for incorporation in Grb2-SH2 domain inhibitors. Part 2.

A series of novel phosphinates, derived from 4-phosphonomethylphenylalanine, are described as isosteres of phosphotyrosine. Benzyl (or alkyl) phosphinomethylphenylalanine derivatives were prepared by alkylation of an amino acid P-H phosphinate.

Collective fear, individualized risk: the social and cultural context of genetic testing for breast cancer.

The purpose of this article is to provide a critical examination of two aspects of culture and biomedicine that have helped to shape the meaning and practice of genetic testing for breast cancer. These are: (1) the cultural construction of fear of breast cancer, which has been fuelled in part by (2) the predominance of a 'risk' paradigm in contemporary biomedicine. The increasing elaboration and delineation of risk factors and risk numbers are in part intended to help women to contend with their fear of breast cancer. However, because there is no known cure or foolproof prevention for breast cancer, risk designations bring with them recommendations for vigilant surveillance strategies and screening guidelines. We argue that these in effect exacerbate women's fears of breast cancer itself. The volatile combination of discourses of fear, risk and surveillance have significant ethical and social consequences for women's lives and well-being. Genetic testing decisions are made within this context; if nurses understand this context they can play an important role in helping women to cope with the anxiety and fear of breast cancer risk.

Prophylaxis for infective endocarditis. Who needs it? How effective is it?

OBJECTIVE: To review guidelines for using antibiotic prophylaxis to prevent infective endocarditis, and to present recent changes and controversies regarding these guidelines. QUALITY OF EVIDENCE: Data are from physiologic and in vitro studies, as well as studies of animal models, and from retrospective analyses of human endocarditis cases. Systematic reviews and guidelines are also examined. As no randomized clinical trials have examined prophylaxis for bacterial endocarditis, many recommendations presented are based on consensus guidelines. MAIN MESSAGE: Antibiotic prophylaxis to prevent bacterial endocarditis should be used in high- and moderate-risk patients with cardiac disease. It should be given before procedures in which bacteremias are likely with organisms that cause endocarditis, such as viridans streptococci. For most procedures, a single dose of amoxicillin (2 g by mouth 1 hour before the procedure) is sufficient to ensure adequate serum levels before and after the procedure. CONCLUSION: Infective endocarditis continues to have high rates of morbidity and mortality. Antibiotic prophylaxis, therefore, is important to combat this preventable disease. For high- and moderate-risk patients with cardiac disease, the cost-benefit ratio favours prophylaxis.

'Because of the risks': how US pregnant women account for refusing prenatal screening.

Most research on prenatal fetal testing in general, and maternal alpha-fetoprotein (AFP) screening in particular, has focused on women who accept and even actively seek prenatal diagnosis. Much of this work suggests that agreeing to prenatal diagnosis is inextricably linked to the processes associated with the 'medicalization' of reproduction and that most women do not see refusal as an option. In contrast, little attention has been paid to women who decline fetal diagnosis. Instead, it is generally assumed that women who do so are resisting this thrust toward medicalization and/or are opposed to abortion. Our research is designed to address this imbalance. We analyze how a group of US women who refused the offer of AFP screening account for their decisions and compare their explanations with those of women who took the test. Contrary to our expectations, we found that refusal did not signify rejection of and/or resistance to the offerings of science and technology. Rather, women who refused often employed biomedical categories, particularly the concept of 'risk', to reject its very offerings. Furthermore, refusers and acceptors were more alike than different in their views on abortion, medicalization and pregnancy. We conclude that the key difference between the two groups lies in their interpretation and application of biomedical concepts and modern risk-assessment.

Screening for cystic fibrosis carrier state.

Carrier screening for cystic fibrosis as part of reproductive health care, including prenatal care, is not the standard of practice at this time. However, a recent National Institutes of Health Consensus Development Conference recommended that cystic fibrosis carrier screening should be offered to adults with a family history of cystic fibrosis, partners of individuals with cystic fibrosis, couples planning a pregnancy, and couples seeking prenatal testing. A workshop convened to discuss the implementation of these recommendations concluded that several issues must be resolved before these recommendations can be implemented. This commentary reviews the discussions that occurred and the conclusions that were reached at this workshop. Some of the subjects considered by the workshop participants were: the goals and outcomes of carrier screening; the continuum from making a test available to offering that test; to whom, when, and how cystic fibrosis testing should be offered; laboratory practice and quality assurance; provider and patient education; and insurance issues. The workshop participants concluded that those populations to whom carrier screening should be offered might include individuals and couples in high-risk groups who seek preconception counseling, infertility care, or prenatal care. High-risk groups include individuals of white northern European or of Ashkenazi-Jewish descent, those whose partners have cystic fibrosis, and those with a family history of cystic fibrosis. Before screening can be offered systematically to these individuals or couples, practice guidelines, educational materials for providers and patients, informed-consent protocols, and laboratory standards for testing must be developed.

Pentafuside (Trimeris).

Pentafuside (T-20) is a 36 amino acid peptide compound under development by Trimeris for the potential treatment of HIV infection, for which it received US FDA fast track designation in February 1999 [313596,182694]. It corresponds to amino acids 638 to 673 of HIV-1(LA1) transmembrane protein, gp41 [238873]. Pentafuside blocks HIV infection, uniquely, by preventing membrane fusion, an essential process in viral replication. In preclinical studies it blocked infection of cells by HIV and prevented the fusion of one HIV-infected cell with another [171217]. In March 1998, Trimeris signed a letter of intent with DuPont Merck Pharm Co to conduct trials of Merck's efavirenz in combination with pentafuside. The trial planned to enroll up to 48 HIV-infected individuals at three sites in the US, who have begun to fail their existing triple combination therapy. Prior exposure to non-nucleoside reverse transcriptase inhibitors and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study is a dose-optimization period that will assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses of pentafuside. After completion of this period, subjects will be eligible to participate in an extension period of at least six months, during which pentafuside will be administered in combination with efavirenz and two protease inhibitors [281696]. The use of pentafuside and truncated peptides in combination with other antiviral agents is claimed in WO-09640191.