"The Warmth of His Continuing Interest": Henry K. Beecher, the Bioethics Revolution, and Pharmaceutical Industry Funding of Academic Medical Science in Cold War America.

This paper examines anesthesiologist Henry K. Beecher's funding relationship with pharmaceutical manufacturer Edward Mallinckrodt, Jr. Beecher is a familiar figure to both medical ethicists and historians of medicine for his role in the bioethics revolution of the 1960s and 1970s. In particular, his 1966 article "Ethics and Clinical Research" is widely considered a turning point in the post-World War II debate about informed consent. We argue that Beecher's scientific interests should be understood in the context of his funding relationship with Mallinckrodt and that this relationship shaped the direction of his work in important ways. We also argue that Beecher's views on research ethics reflected his assumption that collaboration with industry was a normal part of how academic science is conducted. In the conclusion of the paper we suggest that Beecher's failure to consider his relationship with Mallinckrodt as worthy of ethical deliberation has important lessons for academic researchers who collaborate with industry today.

Clinical trials and the origins of pharmaceutical fraud: Parke, Davis & Company, virtue epistemology, and the history of the fundamental antagonism.

This paper describes one possible origin point for fraudulent behavior within the American pharmaceutical industry. We argue that during the late nineteenth century therapeutic reformers sought to promote both laboratory science and increasingly systematized forms of clinical experiment as a new basis for therapeutic knowledge. This process was intertwined with a transformation in the ethical framework in which medical science took place, one in which monopoly status was replaced by clinical utility as the primary arbiter of pharmaceutical legitimacy. This new framework fundamentally altered the set of epistemic virtues-a phrase we draw from the philosophical field of virtue epistemology-considered necessary to conduct reliable scientific inquiry regarding drugs. In doing so, it also made possible new forms of fraud in which newly emergent epistemic virtues were violated. To make this argument, we focus on the efforts of Francis E. Stewart and George S. Davis of Parke, Davis & Company. Therapeutic reformers within the pharmaceutical industry, such as Stewart and Davis, were an important part of the broader normative and epistemic transformation we describe in that they sought to promote laboratory science and systematized clinical trials toward the twin goals of improving pharmaceutical science and promoting their own commercial interests. Yet, as we suggest, Parke, Davis & Company also serves as an example of a company that violated the very norms that Stewart and Davis helped introduce. We thus seek to describe one possible origin point for the widespread fraudulent practices that now characterize the pharmaceutical industry. We also seek to describe an origin point for why we conceptualize such practices as fraudulent in the first place.

Pharmaceutical patenting and the transformation of American medical ethics.

The attitudes of physicians and drug manufacturers in the US toward patenting pharmaceuticals changed dramatically from the mid-nineteenth century to the mid-twentieth. Formerly, physicians and reputable manufacturers argued that pharmaceutical patents prioritized profit over the advancement of medical science. Reputable manufactures refused to patent their goods and most physicians shunned patented products. However, moving into the early twentieth century, physicians and drug manufacturers grew increasingly comfortable with the idea of pharmaceutical patents. In 1912, for example, the American Medical Association dropped the prohibition on physicians holding medical patents. Shifts in wider patenting cultures therefore transformed the ethical sensibilities of physicians.

Factors predisposing to worsening of sleep apnea in response to fluid overload in men.

OBJECTIVES: Obstructive sleep apnea (OSA) is highly prevalent in patients with fluid-retaining conditions. Using bioimpedance measurements, previous studies have shown that the greater the amount of fluid redistributed from the legs to the neck overnight, the greater the severity of OSA. Our objective was to investigate factors that predispose the development or worsening of OSA in response to experimental fluid overload. METHODS: Fifteen normotensive and non-obese adult men with and without OSA underwent polysomnography (PSG) during which normal saline was infused intravenously at a minimal rate to keep the vein open (control) or as a bolus of 22 ml/kg body weight (approximately 2 L) in a random order and crossed over after a week. RESULTS AND CONCLUSIONS: Before and after sleep, neck circumference and bioimpedance were measured to calculate neck resistance, reactance, phase angle, and fluid volume. Subjects who experienced more than a twofold increase in apnea-hypopnea index (AHI) or obstructive AHI from control to intervention and had an AHI>10 during intervention were considered susceptible to the development or worsening of OSA. Baseline neck circumference and phase angle before saline infusion were independently associated with increased susceptibility to developing or worsening OSA in response to saline infusion. In non-obese men, a larger neck circumference and bioimpedance phase angle of the neck, which may be associated with larger pharyngeal tissue content, is associated with increased susceptibility for worsening of OSA in response to fluid overloading.

Medical Narrative and the Rhetoric of Identification: The Many Faces of Anna White Dildane.

When Anna White Dildane, a prostitute and heroin addict, was committed to the Laboratory of Social Hygiene (LSH) in 1917, she was treated by a staff that anticipated the methods of the biopsychosocial model later developed by Engel. That is to say, the staff members believed that Anna's rehabilitation was contingent on a scientific diagnosis of the physical, mental, and social factors that underlay her condition. However, using Anna and the LSH as a case study, we draw from Latour to show the limitations of this "modern" method of diagnosis and treatment that persists today. Using Burke, we advocate for a pragmatic orientation focused on creating rhetorically oriented narratives whose aim is to help patients make judgments about their health and future, namely, by bringing about the experience of "form" capable of constituting new types of identification. Effective medical rhetoric thus adopts a method of persuasion that begins with the narrative and self-understanding of the patient, links aspects of that narrative with the technical expertise of physicians and other health care providers, and crafts a new, more specialized narrative attentive to the desires and constraints of a patient's form of identification that is ultimately the seat of judgment.

Influence of rostral fluid shift on upper airway size and mucosal water content.

STUDY OBJECTIVE: Fluid displacement from the legs during recumbency while in bed might narrow the upper airway (UA) in association with nuchal fluid accumulation that may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to test the hypothesis that rostral fluid displacement from the legs causes a greater decrease in UA cross-sectional area (UA-XSA) and a greater increase in UA mucosal water content (UA-MWC) and internal jugular venous volume (IJVVol) in subjects with OSA than in those without OSA. METHODS: Subjects underwent baseline assessment of leg fluid volume (LFV) measured by bio-electrical impedance, as well as UA-XSA and UA-MWC by magnetic resonance imaging. They were then randomly assigned to a 20-min period either with or without application of lower body positive pressure (LBPP) of 40 mm Hg, followed by a 15-min washout period, after which they crossed over to the other arm of the study. Measurements of LFV, UA-MWC, and UA-XSA were repeated after each arm of the study. RESULTS: In 12 subjects without sleep apnea, UA-XSA increased and UA-MWC decreased significantly, whereas in 12 subjects with OSA, UA-XSA decreased and UA-MWC increased significantly in response to LBPP. The changes in UA-XSA and UA-MWC in response to LBPP differed significantly between the 2 groups (p = 0.006 and p < 0.001, respectively), despite similar changes in LFV and IJVVol. CONCLUSIONS: Our results suggest that rostral fluid shift may contribute to the pathogenesis of OSA at least partly through narrowing of the UA due to transudation of fluid into the UA mucosa.

A randomized, double crossover study to investigate the influence of saline infusion on sleep apnea severity in men.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is commoner in patients with fluid-retaining states than in those without fluid retention, in men than in women, and worsens with aging. In men, OSA severity is related to the amount of fluid shifting out of the legs overnight, but a cause-effect relationship is not established. Our objective was to test the hypothesis that mimicking fluid overload during sleep would increase severity of OSA more in older (≥ 40 years) than in younger men (< 40 years). DESIGN: Randomized, single-blind, double crossover study. SETTING: Research sleep laboratory. PATIENTS OR PARTICIPANTS: Seven older and 10 younger men with non-severe or no sleep apnea, matched for body mass index. INTERVENTIONS: During the control arm, normal saline was infused to keep the vein open. During intervention, subjects received an intravenous bolus of normal saline (22 mL/kg body weight) after sleep onset while they were wearing compression stockings to prevent fluid accumulation in the legs. MEASUREMENTS AND RESULTS: Compared to younger men, infusion of similar amounts of saline in older men caused a greater increase in neck circumference (P < 0.05) and in the AHI (32.2 ± 22.1 vs. 2.2 ± 7.1, P = 0.002). CONCLUSIONS: Older men are more susceptible to the adverse effects of intravenous fluid loading on obstructive sleep apnea severity than younger men. This may be due to age-related differences in the amount of fluid accumulating in the neck or upper airway collapsibility in response to intravenous fluid loading. These possibilities remain to be tested in future studies.

Big pharma and the problem of disease inflation.

Over the course of the past decade, critics have increasingly called attention to the corrosive influence of the pharmaceutical industry on both biomedical research and the practice of medicine. Critics describe the industry's use of ghostwriting and other unethical techniques to expand their markets as evidence that medical science is all-too-frequently subordinated to the goals of corporate profit. While we do not dispute this perspective, we argue that it is imperative to also recognize that the goals of medical science and industry profit are now tightly wed to one another. As a result, medical science now operates to expand disease definitions, lower diagnostic thresholds, and otherwise advance the goals of corporate profit through the redefinition and expansion of what it means to be ill. We suggest that this process has led to a variety of ethical problems that are not fully captured by current critiques of ghostwriting and other troubling practices by the pharmaceutical industry. In our conclusion, we call for physicians, ethicists, and other concerned observers to embrace a more fundamental critique of the relationship between biomedical science and corporate profit.

Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

BACKGROUND: Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. METHODS: Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. RESULTS: Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). CONCLUSIONS: Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. CITATION: Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

The testing of Sanocrysin: science, profit, and innovation in clinical trial design, 1926-31.

This article provides a detailed analysis of the origins and significance of the 1926 clinical trial of Sanocrysin, a gold compound thought at the time to be useful in the treatment of tuberculosis. This experiment is generally considered to be the first clinical trial in the United States that used a formal system of randomization to divide research subjects into treatment and nontreatment groups; it was probably also the first clinical trial in the United States to use placebo shams in a nontreatment control group to overcome the problem of what researchers at the time called "psychic influence." As such, it was an extremely important moment in the history of clinical trial design. Yet, as I argue, the Sanocrysin experiment also needs to be understood in terms of both the regulatory environment at the time and the commercial interests of Parke, Davis & Company, the pharmaceutical manufacturer that was intent on introducing the drug. Although some historians argue that therapeutic reformers in the twentieth century used experimental science to rein in the commercial forces of the market, this article suggests that, at least in this case, the promotion of rigorous clinical science and the pursuit of corporate profit were deeply intertwined.

Contrasting effects of lower body positive pressure on upper airways resistance and partial pressure of carbon dioxide in men with heart failure and obstructive or central sleep apnea.

OBJECTIVES: This study sought to test the effects of rostral fluid displacement from the legs on transpharyngeal resistance (Rph), minute volume of ventilation (Vmin), and partial pressure of carbon dioxide (PCO2) in men with heart failure (HF) and either obstructive (OSA) or central sleep apnea (CSA). BACKGROUND: Overnight rostral fluid shift relates to severity of OSA and CSA in men with HF. Rostral fluid displacement may facilitate OSA if it shifts into the neck and increases Rph, because pharyngeal obstruction causes OSA. Rostral fluid displacement may also facilitate CSA if it shifts into the lungs and induces reflex augmentation of ventilation and reduces PCO2, because a decrease in PCO2 below the apnea threshold causes CSA. METHODS: Men with HF were divided into those with mainly OSA (obstructive-dominant, n = 18) and those with mainly CSA (central-dominant, n = 10). While patients were supine, antishock trousers were deflated (control) or inflated for 15 min (lower body positive pressure [LBPP]) in random order. RESULTS: LBPP reduced leg fluid volume and increased neck circumference in both obstructive- and central-dominant groups. However, in contrast to the obstructive-dominant group in whom LBPP induced an increase in Rph, a decrease in Vmin, and an increase in PCO2, in the central-dominant group, LBPP induced a reduction in Rph, an increase in Vmin, and a reduction in PCO2. CONCLUSIONS: These findings suggest mechanisms by which rostral fluid shift contributes to the pathogenesis of OSA and CSA in men with HF. Rostral fluid shift could facilitate OSA if it induces pharyngeal obstruction, but could also facilitate CSA if it augments ventilation and lowers PCO2.

Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in renal failure.

BACKGROUND: In patients with end-stage renal disease (ESRD), fluid overload may contribute to their high prevalence of obstructive sleep apnea (OSA) by increasing the amount of fluid displaced from the legs into the neck overnight, and possibly compressing the upper airway (UA). Indeed, in ESRD patients, the amount of overnight rostral fluid displacement from the legs is related to the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index, AHI). We, therefore, hypothesized that in ESRD patients, the greater the UA-mucosal water content (UA-MWC) and internal jugular vein volume (IJVVol), the higher the AHI. METHODS: We studied 20 patients with ESRD on thrice weekly hemodialysis who had undergone diagnostic polysomnography (age 41.0 ± 12.3 years, with a body mass index (BMI) of 25.8 ± 6.3 kg/m(2) and an AHI of 20.2 ± 26.8). The leg fluid volume (LFV) was measured by bioelectric impedance. The IJVVol and MWC were measured by UA magnetic resonance imaging (MRI). RESULTS: The only significant independent correlates of the AHI were IJVVol (r = 0.801, P < 0.0001) and UA-MWC (r = 0.720, P = 0.0005) which together explained 72% of its variability. CONCLUSIONS: These data suggest that fluid overload via increased IJVVol, and UA-MWC, contributes to the pathogenesis of OSA in patients with ESRD. These findings help us to explain the high prevalence of OSA in ESRD patients, and attenuation of OSA in association with nocturnal dialysis. They also suggest the need for randomized trials to determine whether more aggressive fluid removal in ESRD patients will alleviate OSA.

Inverse relationship of subjective daytime sleepiness to sympathetic activity in patients with heart failure and obstructive sleep apnea.

BACKGROUND: Patients with heart failure (HF) and obstructive sleep apnea (OSA) are less sleepy than patients with OSA but without HF. Furthermore, unlike the non-HF population, in the HF population, the degree of daytime sleepiness is not related to the apnea-hypopnea index (AHI). The sympathetic nervous system plays a critical role in alertness. HF and OSA both increase sympathetic nervous system activity (SNA) during wakefulness. We hypothesized that in patients with HF and OSA, the degree of subjective daytime sleepiness would be inversely related to SNA. METHODS: Daytime muscle SNA (MSNA) was recorded in patients with HF and OSA. Subjective daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS). RESULTS: We studied 27 patients with HF and OSA and divided them into two groups based on the median ESS score: a less sleepy group, with an ESS score < 6 (n = 13), and a sleepier group, with an ESS score ≥ 6 (n = 14). The less sleepy group had higher MSNA than did the sleepier group (82.5 ± 9.9 bursts/100 cardiac cycles vs 69.3 ± 18.6 bursts/100 cardiac cycles; P = .037) and a longer sleep-onset latency (33 ± 29 min vs 14 ± 13 min; P = .039). The ESS score was inversely related to MSNA (r = -0.63; P < .001) but not to the AHI, arousal index, or indices of oxygen desaturation. CONCLUSIONS: In patients with HF and OSA, the degree of subjective daytime sleepiness is inversely related to MSNA. This relationship is likely mediated via central adrenergic alerting mechanisms. These findings help to explain the previously reported lack of daytime hypersomnolence in patients with HF and OSA.

A thing patented is a thing divulged: Francis E. Stewart, George S. Davis, and the legitimization of intellectual property rights in pharmaceutical manufacturing, 1879-1911.

This article examines the efforts of pharmacist and physician Francis E. Stewart to legitimize the commercial introduction of new drugs by reinterpreting the ethical status of patent rights in pharmaceutical manufacturing. I argue that patents had long been understood by the orthodox medical community as an unethical form of medical monopoly and that, as a result, drug companies that marketed their goods primarily to physicians in the years immediately following the Civil War had little room to develop or introduce new products. In collaboration with George S. Davis and the pharmaceutical manufacturing firm Parke, Davis, & Company, Stewart worked to redefine patents as an ethical means of encouraging scientific and commercial innovation. In doing so, he sought to reconcile medical science and commerce so that they were mutually beneficial to one another. However, I also suggest that his efforts had an ironic effect in that they helped legitimatize a form of patent protection that Stewart himself came to believe to be unethical in nature.

Mass-producing the individual: Mary C. Jarrett, Elmer E. Southard, and the industrial origins of psychiatric social work.

This article examines the origins of psychiatric social work in the United States between 1912 and 1930. It argues that the establishment of the field needs to be understood in terms of Mary C. Jarrett and Elmer E. Southard's efforts to apply psychiatric techniques to the mental health problems of industrial employees. It further argues that Jarrett and Southard worked to develop a treatment approach to the mental health problems of industrial workers that they termed "individualization," and that despite their assumptions about the future of psychiatric social work the field was never established as an important part of industrial management.