Gender paradox in cardiac calcium deposits in middle-aged and elderly patients: mitral annular and coronary calcifications interrelationship

OBJECTIVES: mitral annular calcification (MAC) occurs mainly in middle-aged and elderly patients and can lead to serious clinical consequences. Male predominance in the prevalence of coronary disease is well-established. Paradoxically, the prevalence of MAC, which is theoretically based on the same etiological mechanisms as coronary atherosclerosis, seems to be predominant in postmenopausal women. The goal of this work was to investigate gender influences on interrelationship between MAC and coronary calcifications (CC) in the same population of middle-aged and elderly patients with increased cardiovascular risk. METHODS: the study comprised 522 patients (284 men and 238 postmenopausal women, aged 52-80 years, mean 65+/-6), who were recruited to the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) study in our region. They underwent both fast spiral computed tomography of the heart and echo-Doppler. MAC was defined as advanced when its thickness was > or =5mm; otherwise it was defined as trivial. RESULTS: there were 37 (16%) women and 25 (9%) men with advanced MAC (AMAC), 97 (41%) women and 118 (42%) men with trivial MAC and 104 (44%) women and 141 (50%) men without MAC. The prevalence of any type of CC was significantly higher among men (P=0. 001). In sharp contrast to the distinct male predominance in coronary disease, AMAC was more prevalent among women. In patients without CC prevalence was 9 and 4%, increasing to 16 and 8% in those with nonsevere CC and to 38 and 14% in patients with severe CC, respectively (P=0.001). Multivariate analysis showed that AMAC can predict the presence of severe CC in women and men, with OR of 4.1 and 2.6 (CI 1.2-14.8 and 1.0-10.6) and coronary disease with OR of 2. 5 and 2.5 (CI 0.6-10.6 and 1.0-6.4), respectively. CONCLUSIONS: AMAC signifies a high probability of coronary atherosclerosis in patients of both genders. The inverted gender predominance in the prevalence of annular calcification and CC could be explained by additional etiological (likely osteoporotic) mechanisms of MAC development among postmenopausal women.     

EEG findings and language patterns in autistic children: clinical correlations

Several authors have used the EEG as a diagnostic tool to identify distinctive patterns of cerebral dysfunction in autistic children. However, evidence is needed to support the hypothesis that their level of functioning correlates with their EEG profile. In this study EEG's were obtained in 17 autistic children without sedation and following sleep deprivation. These children were also evaluated in a double blind procedure with regard to their speech and communication abilities. We did not find a statistically significant correlation between EEG changes and speech performance. None of the autistic children using an augmentative system of communication had any EEG abnormalities. However, a normal EEG is not sufficient to predict successful response to communication therapy. Since the effect of sedative drugs on brain electrical activity limits the value of tracings, we recommend the sleep deprivation techniques when "difficult" children have to undergo EEG testing. Parents' or guardians' participation during the procedure is encouraged.     

Experimental evidence of physician social preferences

Physicians’ professional ethics require that they put patients’ interests ahead of their own and that they should allocate limited medical resources efficiently. Understanding physicians’ extent of adherence to these principles requires understanding the social preferences that lie behind them. These social preferences may be divided into two qualitatively different trade-offs: the trade-off between self and other (altruism) and the trade-off between reducing differences in payoffs (equality) and increasing total payoffs (efficiency). We experimentally measure social preferences among a nationwide sample of practicing physicians in the United States. Our design allows us to distinguish empirically between altruism and equality–efficiency orientation and to accurately measure both trade-offs at the level of the individual subject. We further compare the experimentally measured social preferences of physicians with those of a representative sample of Americans, an “elite” subsample of Americans, and a nationwide sample of medical students. We find that physicians’ altruism stands out. Although most physicians place a greater weight on self than on other, the share of physicians who place a greater weight on other than on self is twice as large as for all other samples—32% as compared with 15 to 17%. Subjects in the general population are the closest to physicians in terms of altruism. The higher altruism among physicians compared with the other samples cannot be explained by income or age differences. By contrast, physicians’ preferences regarding equality–efficiency orientation are not meaningfully different from those of the general sample and elite subsample and are less efficiency oriented than medical students.

In a classic article, Kenneth Arrow (1) argued that asymmetric information pervades the health-care market. Patients rely on physicians’ expert knowledge in planning their medical care. Health insurers and government agencies (Medicare and Medicaid) largely rely on physicians to decide which treatments are appropriate for their patients. This deference to physicians’ authority may be justified given their superior expertise and informational advantages (2). However, the dual role of recommending and providing treatments creates opportunities for physicians to place their interests ahead of their patients’ interests, for example by recommending profitable tests and treatments that offer little or no health benefits. A second risk is more subtle. Physicians must trade off their individual patients’ interests in getting care, even if the benefit is likely to be small, against society’s interest in allocating limited medical resources efficiently, in order to generate the greatest benefits for the overall health of a population.The norms of physician professionalism—including, in particular, the patient-centered norms that constitute physicians’ traditional professional ethic—are intended to address the risk of selfishness. Arrow argues that due to information asymmetry, the principle of“buyer beware” that governs ordinary consumer markets should be replaced, in health care, by the physicians’ professional responsibility to put patients’ interests ahead of their own (1). Physician leaders publicly promote the importance of professionalism, while exhorting physicians to act altruistically. For example, the editors of the New England Journal of Medicine have asserted that “medicine is one of the few spheres of human activity in which the purposes are unambiguously altruistic” (3), while the American Board of Internal Medicine similarly asserts that “altruism is the essence of professionalism … the best interest of patients, not self-interest, is the rule” (4). On the other hand, empirical studies have suggested that, at least in some situations, some physicians create “supplier-induced demand,” which influences a patient’s demand for care “against the physician’s interpretation of the best interest of the patient” (5), contributing to skepticism about whether physicians do in fact behave altruistically. [Such skepticism is not limited to medicine. Legal ethics, for example, has long sought to control lawyers’ abuse of discretion through professional norms of client loyalty and care (6). But skeptics have cast these norms as self-serving, and the law governing lawyers increasingly subjects them to elaborate institutionalized mechanisms of bureaucratic control.]While the effects of professional norms on physician behavior are difficult to measure directly, a clearer understanding of physicians’ social preferences can help to illuminate whether professional norms and physicians’ individual preferences are oppositional or aligned. Our study therefore helps to evaluate the likely effectiveness of both professional norms and the turn to bureaucracy. While altruism and related professional norms are important in many other professions (7), the distinct characteristics of the market for medical care, namely information asymmetry and uncertainty in the relationship between medical treatments and patient outcomes (1), render it especially critical to study these issues among physicians.Health care systems in the US and elsewhere address the second risk—concerning efficiency—in more complex ways. Although professional ethics give physicians a responsibility to conserve scarce medical resources (8), the norm that directs individual physicians to put their patients first may render a norm-based approach inadequate to the problem of efficiency (9). Health insurers therefore use bureaucratic mechanisms and financial incentives to manage the information asymmetry between a physician who knows the specific patient’s situation and the insurer which does not (9).^*We deploy an incentivized economic experiment to investigate both altruism (the trade-off between self and other) and equality–efficiency orientation (the trade-off between reducing self–other differences in payouts and increasing payout totals) in practicing US physicians, and we compare our results with analogous experiments that measure parallel behaviors in other populations. A vast literature considers social preferences, and laboratory experiments have been very fruitful in both establishing the empirical reliability of such preferences and directing theoretical attention to them. [We will not attempt to review the enormous body of work in behavioral and experimental economics on social preferences. Camerer (10) provides a comprehensive discussion, if now somewhat dated, of the vast body of experimental and theoretical research in economics focusing on dictator, ultimatum, and trust games. Engel (11) provides the most comprehensive meta-study of dictator games.] After presenting our results, we relate them to the results from prior work that are particularly relevant to our study (Discussion). We note that the social preferences of physicians and professionals more generally remain relatively understudied, and our discussion of the relationship between our study and prior work explains the specific contributions that we make.Our sample consists of 284 physicians from 36 medical groups around the United States, including physicians in primary care (internal medicine and family medicine) and cardiology, and physicians in private practices and employed by hospitals. Our experiment gives subjects broad discretion to implement their preferences, free from bureaucratic control or even surveillance. Our results therefore inform the question whether norms are likely to affect physician choices along both dimensions of behavior. Our study measures altruism in a large multisite sample of practicing physicians and measures both dimensions of social preferences.Our experiment asked subjects to make trade-offs between their own self-interest and the interest of an anonymous other and, at the same time, between equality and efficiency. These two aspects of social preferences often operate together, but they remain conceptually distinct. [Social preferences can be weighted toward equality (reducing differences in payoffs) or weighted toward efficiency (increasing total payoffs) and range from pure utilitarian to maxmin or Rawlsianism. As the dispute between Harsanyi (12, 13) and Rawls (14) shows, fair-minded people (who are all perfectly impartial between self and other) can disagree about how to trade off equality and efficiency. The work of Harsanyi and Rawls, and of the many others who have followed them, has had broad-reaching influence across many disciplines, including philosophy, economics, and law.] To capture both of these features in our experiment, we employ a modified dictator game (15–17) in which we ask physicians to allocate real money between themselves and an anonymous other drawn from a broadly representative sample of the US population. Our experiment presents subjects with allocation decisions in which the “price of giving” varies across decision problems—sometimes the subject may need to sacrifice more than a token (the experimental currency)—to give a single token to other (the recipient); in other decisions, it may cost only a fraction of a token. These decisions are made through an intuitive “point-and-click” graphical interface in which the choices are represented as a budget line where each point represents a possible allocation. The slope of the line captures the price of giving tokens to other.^†Intuitively, this method allowed us to collect a rich dataset capable of measuring both altruism and equality–efficiency orientation at the level of the individual subject. [The importance of studying individual heterogeneity in social preferences is emphasized by Andreoni and Miller (17). Because of this heterogeneity, it is necessary to investigate behavior at an individual level. Our experimental design allows subjects to make numerous choices over a wide range of budget lines, and this yields a rich dataset that is well-suited to analysis at the individual level. It is clearly advantageous to estimate individual-level parameters and then generate individual-level distributions of the estimations rather than to pool data and then estimate population-level parameters.] The degree of altruism is reflected in the amount subjects give on average, whereas equality–efficiency orientation is captured by how subjects respond to the price of giving. Increasing the fraction of the budget spent on other as the price of giving increases indicates social preferences weighted toward equality (reducing the difference in payoffs between self and other), whereas decreasing it when the price of giving increases indicates social preferences weighted toward efficiency (increasing the total payoffs to self and other). We rely on techniques developed in our prior work (15, 16, 18) to evaluate the consistency of physicians’ choices (i.e., whether they reflect a complete and transitive preference ordering) and to explore the structure of the social utility functions that rationalize the observed data.We further compare physicians’ preferences with preferences previously measured in three other populations using equivalent experiments: 1) a broadly representative sample of US adults (18), 2) an “elite” subsample of those who hold a graduate degree and have an annual household income over $100,000 (15, 18), and 3) a sample of medical students from nine schools around the United States (19, 20). The social preferences of these populations provide important benchmarks against which physicians’ social preferences can be assessed; furthermore, the comparison with medical students may shed light on whether physicians’ distinctive social preferences reflect a “selection effect” based on who enters medicine or a “treatment effect” of practicing medicine.^‡We begin our analysis of the experimental data by using classical revealed preference theory (21–23) to test whether subjects’ choices are consistent with the essence of all traditional models of economic decision-making—utility maximization.^§ Our physician subjects exhibit a remarkably high degree of consistency when compared with other populations, including medical students and also students from Yale Law School (YLS), the population that had exhibited the highest degree of consistency in prior experiments (15). [In our subsequent analysis, we do not draw detailed comparisons between our physician sample and the sample YLS students (15). The experimental design in Fisman et al. (15) differs from the current one in that the YLS student subjects were asked to allocate money between themselves and another student, rather than an individual drawn from a sample broadly representative of the US adults.] This result reveals that our physician subjects are highly adept at implementing a consistent, well-behaved social preference ordering. This makes it natural to estimate—at the level of the individual subject—the substantive social preferences that physicians display.We then estimate social preferences at the level of the individual physician using a constant elasticity of substitution (CES) utility function commonly employed by economists in demand analysis. The CES functional form is appealing because the degree of altruism and equality–efficiency orientation are each independently represented in a precise and transparent manner through its two parameters, which we estimate separately for each subject (further details on the CES specification and estimation are provided in Empirical Framework).We find that physicians are more altruistic than any other population, while physicians’ preferences concerning the trade-off between equality and efficiency are almost indistinguishable graphically from the preferences of the American Life Panel (ALP) elites and also the broader ALP sample. These findings on physicians’ distinctive social preferences have direct and concrete implications for professionalism, incentives, and bureaucratic rules directed at physicians. Insofar as physicians are altruistic, they may be more likely to live up to the professional ideal of putting patients’ interests ahead of their own. At the same time, altruism as captured in our experiment is far from ubiquitous, even among physicians and, furthermore, physicians’ efficiency orientation is indistinguishable from than that of the general population. Taken together, our findings suggest that the ideal of physician professionalism—putting the patient first—is not merely a self-serving myth but that other mechanisms may be required to support the quality of medical care and to promote efficient allocation of medical resources.     

Type II antithrombin deficiency caused by a large in‐frame insertion: structural,functional and pathological relevance

Summary. Background: The metastable native conformation of serpins is required for their protease inhibition mechanism, but also renders them vulnerable to missense mutations that promote protein misfolding with pathological consequences. Objective: To characterize the first antithrombin deficiency caused by a large in‐frame insertion. Patients/Methods: Functional, biochemical and molecular analysis of the proband and relatives was performed. Recombinant antithrombin was expressed in HEK‐EBNA cells. Plasma and recombinant antithrombins were purified and sequenced by Edman degradation. The stability was evaluated by calorimetry. Reactive centre loop (RCL) exposure was determined by thrombin cleavage. Mutant antithrombin was crystallized as a dimer with latent plasma antithrombin. Results: The patient, with a spontaneous pulmonary embolism, belongs to a family with significant thrombotic history. We identified a complex heterozygous in‐frame insertion of 24 bp in SERPINC1, affecting strand 3 of β‐sheet A, a region highly conserved in serpins. Surprisingly, the insertion resulted in a type II antithrombin deficiency with heparin binding defect. The mutant antithrombin, with a molecular weight of 59 kDa, had a proteolytic cleavage at W49 but maintained the N‐terminal disulphide bonds, and was conformationally sensitive. The variant was non‐inhibitory. Analysis of the crystal structure of the hyperstable recombinant protein showed that the inserted sequence annealed into β‐sheet A as the fourth strand, and maintained a native RCL. Conclusions: This is the first case of a large in frame‐insertion that allows correct folding, glycosylation, and secretion of a serpin, resulting in a conformationally sensitive non‐inhibitory variant, which acquires a hyperstable conformation with a native RCL.     

Acute surgical unit safely reduces unnecessary after-hours cholecystectomy

Introduction

The acute surgical model has been trialled in several institutions with mixed results. The aim of this study was to determine whether the acute surgical model provides better outcomes for patients with acute biliary presentation, compared with the traditional emergency surgery model of care.

Methods

A retrospective review was carried out of patients who were admitted for management of acute biliary presentation, before and after the establishment of an acute surgical unit (ASU). Outcomes measured were time to operation, operating time, after-hours operation (6pm – 8am), length of stay and surgical complications.

Results

A total of 342 patients presented with acute biliary symptoms and were managed operatively. The median time to operation was significantly reduced in the ASU group (32.4 vs 25.4 hours, p=0.047), as were the proportion of operations performed after hours (19.5% vs 2.5%, p<0.001) and the median length of stay (4 vs 3 days, p<0.001). The median operating time, rate of conversion to open cholecystectomy and wound infection rates remained similar.

Conclusions

Implementation of an ASU can lead to objective differences in outcomes for patients who present with acute cholecystitis. In our study, the ASU significantly reduced time to operation, the number of operations performed after hours and length of stay.