Excerpt For short-term studies of sick people hospitalized because of illness, physicians can concentrate on the scientific problems under investigation. In such circumstances, the investigators ne...

The physiological model had a series of beautifully conceived, carefully planned, and splendidly executed equations that described the diffusion of fluids through the human body. The mathematical product is a numerical probability–utility score that has no direct clinical or intuitive meaning; but the probability–utility product scores associated with diverse outcomes are then folded back or arranged in various other ways. For the interventional decisions of patient care, the basic sciences are sometimes regarded as statistics, economics and sociology. Since physiology, biochemistry, and molecular biology were historically derived from clinical medicine, many intellectual connections still remain; and the applications of these sciences can be meaningfully arranged. The set of 'basic' fields—in statistics, economics, and sociology—were developed on their own, however, without any direct relationship to clinical challenges. Clinicians should make use of all the effective consultative help they can get, but should not abandon fundamental challenges that require direct clinical solutions from wise clinical intellects.

THE INTELLECTUAL CRISIS IN CLINICAL SCIENCE: MEDALED MODELS AND MUDDLED METTLE ALVAN R. FEINSTEIN* Amid the many problems in cost of care, distribution of manpower, ethics of abortion and euthanasia, and other crises of modern clinical medicine, another important problem seldom receives attention. The additional crisis, which is the subject of this essay, is intellectual. It arises from the conceptual models used in clinical thinking. At any era in the history of medicine, clinicians have relied on certain basic ideas to act as theoretical models for reasoning about the manifestations , cause, and treatment of disease. Although seemingly satisfactory during the era in which they were used, most of the models were later found to be defective. Some were overtly wrong; others were superseded by improvements brought from advances in science and technology . For example, the basic model of humoral derangements served for many centuries as a theoretical concept that united the cause and treatment of disease. In that model, disease was caused by imbalances in the four humors of blood, phlegm, black bile, and yellow bile. The imbalances were rectified by appropriate treatment with bloodletting, blistering, purging, and puking. In modern medical activities, a different set of conceptual models has been developed for ideas about the diseases, decisions, and data evaluated by practicing clinicians and for beliefs about the goals and basic sources of clinical science. Like the well-established concepts of the past, many of the current models have been "medaled" by their widespread acceptance and general popularity. Yet each model has some outstanding defects that will require major improvements for clinical practice to Supported in part by the Robert WoodJohnson Foundation grant 6309 and the Andrew W. Mellon Foundation. The opinions, conclusions, and proposals in this text are those of the author and do not necessarily represent the views of either foundation. *School of Medicine, Yale University, 1-456 SHM, P.O. Box 3333, New Haven, Connecticut 06510.© 1987 by The University of Chicago. AU rights reserved. 0031-5982/87/3002-0520$01 .00 Perspectives in Biology and Medicine, 30, 2 ¦ Winter 1987 \ 2 15 deal successfully with its current and future challenges as a humanistic science. My purpose in this essay is to discuss the models, the defects, and the improvements. 1. The Basic Sources of Clinical Science Until the beginning of the nineteenth century, clinical medicine was regarded as a basic source of fundamental scientific challenges. The challenges had explanatory goals: to understand the disordered structures and functions that were mechanisms of human disease. In pursuit of the explanations, scholarly clinicians left the bedside to investigate pathologic anatomy in dead human bodies, physiologic abnormalities in experimental animals, and chemical or microbial phenomena in various laboratory arrangements. As knowledge accumulated and opportunities increased, four new scientific domains—pathology, physiology, biochemistry, and microbiology —evolved from their basic sources in clinical research. With further development during the first half of the twentieth century, these new domains became separate "preclinical sciences." Each domain contained a mixture of concepts, some coming from direct exploration of clinically oriented questions, others arising nonclinically in work of the domain itself. After World War II, the funding for this type of clinically derived research was sharply increased; and the research changed its orientation . The preclinical sciences became detached from their clinical origins and were converted into "basic biomedical sciences" with goals that often no longer aimed at mechanisms of disease, with investigators who often had no clinical training or responsibilities, and with results that often had no overt relationship to clinical phenomena. The maintenance of a clinical connection for the new activities was assigned to clinical investigators . Well supported and abundant at medical schools, the clinical investigators learned the advances of the "basic sciences," tried to apply them in suitable research with patients, and taught the "basic" scientific ideas as correlated explanations for the mechanisms of human disease. The magnificent achievements and benefits that have come from basic biomedical science are beyond dispute, but the new orientation led to several unanticipated problems in clinical medicine. One major problem , to be discussed later, is that the new scientific models, despite their splendid contributions in explaining the pathophysiology ofclinical phenomena , were not pertinent for the managerial issues...

Classical molecular genetics uses stringent selective conditions to identify mutants with distinct phenotypic responses. Mutations giving rise to less pronounced phenotypes are often missed. However, to gain systems-level insights into complex genetic interaction networks requires genome-wide assignment of quantitative phenotypic traits. In this paper, we present a quantitative selection approach coupled with transposon sequencing (QS-TnSeq) to globally identify the cellular components that orchestrate susceptibility of the cell cycle model bacterium Caulobacter crescentus toward bacteriophage φCbK infection. We found that 135 genes representing 3.30% of the Caulobacter genome exhibit significant accumulation of transposon insertions upon φCbK selection. More than 85% thereof consist of new factors not previously associated with phage φCbK susceptibility. Using hierarchical clustering of dose-dependent TnSeq datasets, we grouped these genes into functional modules that correlate with different stages of the φCbK infection process. We assign φCbK susceptibility to eight new genes that represent novel components of the pilus secretion machinery. Further, we demonstrate that, from 86 motility genes, only seven genes encoding structural and regulatory components of the flagellar hook increase phage resistance when disrupted by transposons, suggesting a link between flagellar hook assembly and pili biogenesis. In addition, we observe high recovery of Tn5 insertions within regulatory sequences of the genes encoding the essential NADH:ubiquinone oxidoreductase complex indicating that intact proton motive force is crucial for effective phage propagation. In sum, QS-TnSeq is broadly applicable to perform quantitative and genome-wide systems-genetics analysis of complex phenotypic traits.

When rising rates of occurrence are reported for a particular disease, clinicians often cannot determine whether the disease has increased in actual occurrence or in the improved detection provided by better diagnostic technology and expanded access to medical care. The epidemiologic use of necropsy data, which might help answer these questions, has been inhibited by fears of bias in demographic and clinical selection of patients for necropsy. The demographic problem can be managed by suitable adjustment and standardization of the disease rates found at necropsy, and the clinical problem can be reduced or avoided by studying the rates with which the disease is found unexpectedly in necropsies performed for other, unrelated clinical reasons. The results, obtained in population groups "screened" via necropsy, can suggest the magnitude of the "undetected reservoir" that coexists and supplements the rates of reported occurrence for a disease. In a study of necropsies at Yale\p=m-\NewHaven (Conn) Hospital from 1972 to 1981, the necropsy detection rates for lung cancer were slightly higher for women than for men, and were substantially higher for both genders than the customarily reported rates in the general population. The results suggest that the reported rates may continue to rise in both genders until they become essentially equal at a size approximating that of the currently undetected reservoir. The "epidemiologic necropsy" offers a potentially valuable method to help distinguish the true occurrence rates of disease from the changes attributable to improved diagnostic detection with modern technology. (JAMA 1987;258:331-338)

A system of auxometric staging for the clinical growth rate of breast cancer can be created by considering the observed duration of the tumor and the concomitant occurrence of transition events. In an inception cohort of 219 women with histologically confirmed breast cancers that had first been treated at the Yale-New Haven Hospital during the interval 1962 to 1964, the overall five-year survival rate was 63%. Within categories of the three new auxometric stages, the five-year survival rates were as follows: slow, 37/45 (82%); intermediate, 85/133 (64%); and rapid, 15/41 (37%). These auxometric categories were combined with conventional TNM ana- tomic categories to form a composite anatomic-auxometric system of four stages, A through D. A particularly striking feature of the new composite sys- tem was the demarcation of 22 patients in stage A who had a 100% five-year survival rate, regardless of whether mastectomy was simple or radical. In stages B, C, and D, radical mastectomy appeared superior to simple mastec- tomy, but the results may have been affected by bias in selecting patients ac- cording to prognostic features that are not included in the composite new stages. The results are pertinent in therapeutic decisions for individual patients, in the design of large-scale therapeutic trials, and in biologic correlation of diverse laboratory research. Because a cancer has biologic function as well as anatomic structure, both the function and the structure require appropri- ate analytic attention. The exclusively anatomic categories that form the basis of conventional systems of staging for breast cancer can be complemented, augmented, and

Although systemic corticosteroids are widely used in treating stable chronic obstructive pulmonary disease (COPD), the evidence for their efficacy is still disputed. To reappraise this evidence, the authors used a new analytic strategy in which the 14 available randomized clinical trials were evaluated according to a methodologic "review of systems" and an examination of the statistical precision of the outcome results. Although none of the trials satisfied all of the methodologic criteria for both validity and clinical pertinence, the trials finding steroids efficacious were generally better designed and more statistically precise than trials failing to show efficacy. The authors propose a set of five main methodologic guidelines that require a stable baseline state, a crossover design with suitable washout, adequate doses of corticosteroids, pragmatic designs, and comprehensive choices of outcome events. Attention to these guidelines can help improve both design and evaluation for future trials of systemic steroids for stable COPD.

Abstract In his comment on Victor Fuch's essay, the late Alvan Feinstein raised the question of whether government‐sponsored programs of “health promotion” are always good for well‐being.

In a previous study of three types of global scales we found that verbal rating scales were particularly reliable for rating auditory stimuli. We now wanted to check the performance of the scales for rating experimentally controlled visual stimuli. We used a prospective, experimentally controlled, clinimetric study, which was conducted at the Department of Psychiatry of the Autonomous University of Puebla Medical School in the state capital city of Puebla, Mexico. A total of 20 fifth-year medical students participated in the study. Visual stimuli consisted of 15 cards with five different intensities on the gray-to-black scale, administered randomly in three sessions to each subject. With regard to main outcome measurement, validity and consistency indices were determined for visual analog scale (VAS), numerical rating score (NRS), and verbal rating scale (VRS) to rate visual stimuli. For validity, correlation coefficients between scales and reference standard were high, especially in VRS (r = 0.902). For consistency, VRS had highest kappa value (kw = 0.71) for interobserver variability. Three instruments could be hierarchically ranked for their indices of validity and consistency. Being more consistent than VAS and NRS, VRS merits more frequent usage in clinical research.

Objectives: To examine whether physical and cognitive impairments explain low use of beta-blockers in elderly patients and whether functionally impaired older adults have improved survival if a beta-blocker is prescribed at hospital discharge.Design: Cross-sectional and retrospective cohort study.Setting: Acute care hospitals in the United States.Participants: National cohort of 45,370 elderly acute myocardial infarction survivors, with no chart-documented contraindications to beta-blocker treatment.Measurements: The main outcome measures were beta-blocker prescription at hospital discharge and 1-year survival.Results: Fifty percent (n=22,683) of eligible patients were prescribed a beta-blocker at discharge. Older age and functional impairments (incontinence, mobility impairment, and cognitive impairment) were independently associated with decreased use of beta-blockers. The odds ratios for prescribing a beta-blocker at hospital discharge were 0.82 (95% confidence interval (CI)=0.77-0.86), 0.63 (95% CI=0.56-0.71), and 0.40 (95% CI=0.32-0.51) for persons with one, two, and three impairments, respectively, compared with those with no impairments. In survival analysis, patients prescribed a beta-blocker were 21% less likely than nonrecipients to die within 1 year of follow-up (relative risk=0.79, P=.0001). Similar survival benefit was observed in patients with and without functional impairments.Conclusion: This study shows a strong association between functional impairment and the use of beta-blockers after acute myocardial infarction in elderly patients. The results suggest that increasing use of beta-blockers in this group provides an opportunity to improve outcomes.

234 WHEN I ENTERED MEDICAL SCHOOL in 1948, specialization and group practice were developing rapidly, but most physicians were still solo practitioners, often maintaining their office in their home. As proprietors of this cottage industry, physicians were usually financially comfortable, but not rich.They were respected, often revered members of their community, making useful contributions to the health and lives of their patients. For most patients, the relationship with their doctor was mutually trusting and gratifying. Five decades later, the medical profession has undergone changes much more drastic than the social transformation that raised physicians’ incomes from relative poverty in the 19th century to modest affluence in the first half of the 20th (Starr 1982).The changes of the past 50 years can be quickly summarized with the following three vignettes of conversation that might occur when someone met a doctor on a social occasion. In 1957, the statement might be,“So you’re a doctor. Hey doc, what do you think about this rash on my arm?” In 1977, the speaker might say,“So you’re a doctor.Where’s your Porsche?” In 1997, the comment might be,“So you’re a doctor. Let me tell you what some damned doctor and health care plan did to my sister.”

OBJECTIVETo estimate the relative risk for otitis media (OM) in children from environmental tobacco smoke (passive exposure), maternal smoking during pregnancy (gestational exposure), or both.DESIGNAnalysis of data from a national cross-sectional health survey, utilizing questionnaire information and serum cotinine measurements.PARTICIPANTSChildren younger than 12 years (N = 11 728) in the Third National Health and Nutrition Examination Survey (NHANES III), conducted from 1988-1994.MAIN OUTCOME MEASURESOccurrence and recurrence of ear infections.RESULTSThe cumulative incidence of ear infections was 69%. Of all participants, 38% were exposed to passive smoke, 23% were exposed to gestational smoke, and 19% were exposed to combined passive and gestational smoke. The occurrence of any ear infection was not increased by passive smoke exposure (adjusted risk ratio [RR], 1.01; 95% confidence interval [CI], 0.95-1.06), but was slightly increased by gestational (adjusted RR, 1.08; 95% CI, 1.01-1.14) and combined (adjusted RR, 1.07; 95% CI, 1.00-1.14) smoke exposures. The risk of recurrent ear infections (> or = 6 lifetime episodes) was significantly increased with combined smoke exposure (adjusted RR, 1.44; 95% CI, 1.11-1.81). Other risk factors for ear infection identified in multivariable analysis were race/ethnicity, poverty-income ratio of 2.00 or more, attendance in day care, history of asthma, and presence of allergic symptoms.CONCLUSIONSPassive smoke exposure was not associated with an increased risk of ever developing an ear infection in this study. The increased risk found with gestational and combined smoke exposures has marginal clinical significance. For recurrent ear infections, however, combined smoke exposure had a clinically and statistically significant effect.

Journal of Evaluation in Clinical PracticeVolume 8, Issue 2 p. 139-141 Will clinicians’ challenges be solved by another theoretical model? Commentary on Sweeney & Kernick (2002), Clinical evaluation: constructing a new model for post-normal medicine. Journal of Evaluation in Clinical Practice 8, 131–138 Alvan Feinstein R. MD MACP, Alvan Feinstein R. MD MACP Sterling Professor of Medicine and Epidemiology, Yale University School of Medicine, USASearch for more papers by this author Alvan Feinstein R. MD MACP, Alvan Feinstein R. MD MACP Sterling Professor of Medicine and Epidemiology, Yale University School of Medicine, USASearch for more papers by this author First published: 13 June 2002 https://doi.org/10.1046/j.1365-2753.2002.00325.xCitations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume8, Issue2Special Issue: Evidence Based MedicineMay 2002Pages 139-141 RelatedInformation

Despite extensive growth in recent years, the field of "quality-of-life" appraisal still evokes debate about basic perception of the concept and is accompanied by a plethora of indexes for measurement. One prime reason for the problems is that the measurements have been transferred from two separate sources - medical health status indexes and social-science population indexes - neither of which was designed for appraising the particular personal distinctions of the way people feel about their own quality of life. When regulatory and commercial incentives were offered for measuring patients' quality of life, it became appraised with the indexes available from the medical and psychosocial sources, even though neither set of indexes was specifically intended for that purpose. They are not developed from the basic principle that a person's "quality of life" is a state of mind, not a state of health, which is uniquely perceived by that person, and which will not be appropriately appraised unless the most cogent personal components are allowed suitable expressions. An approach that lets patients state their own opinions directly can offer the "face validity" or "common sense" that now seems absent from the generally applied measurements.