Shai Mulinari

Monoamine Theories of Depression: Historical Impact on Biomedical Research

Monoamine theories associate depression with reduced brain monoamine levels. These theories achieved broad popularity in the mid-1960s. The present article reviews the historical development of monoamine theories and their subsequent impact on biomedical research. Alleged divisions between West European and US researchers over competing versions of the theories are investigated using bibliometrics. Subsequently, the application of monoamine theories in the NIMH Collaborative Program on the Psychobiology of Depression is covered. The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas.

Expression and regulation of Spätzle-processing enzyme in Drosophila

The Drosophila melanogaster Toll receptor controls embryonic dorsal‐ventral axis formation and is crucial for the innate immune response. In both cases, Toll is activated by the enzymatically cleaved form of its ligand Spätzle (Spz). During axis formation, Spz is cleaved by the maternally provided serine protease Easter while the Spätzle‐processing enzyme (SPE) activates Spz after infection. We confirm the role of SPE in immunity and show that it is a zygotic gene specifically expressed in immune tissues implying that the dual activation of Spz is achieved by differential spatiotemporal expression of two similar but distinct serine proteases.

Misleading Advertising for Antidepressants in Sweden: A Failure of Pharmaceutical Industry Self-Regulation

Background The alleged efficacy of pharmaceutical industry self-regulation has been used to repudiate increased government oversight over promotional activity. European politicians and industry have cited Sweden as an excellent example of self-regulation based on an ethical code. This paper considers antidepressant advertising in Sweden to uncover the strengths and weaknesses of self-regulation. Methodology We analyzed all antidepressant advertisements in the Swedish Medical Journal, 1994–2003. The regulation of these advertisements was analyzed using case reports from self-regulatory bodies. The authors independently reviewed this material to investigate: (1) extent of violative advertising; (2) pattern of code breaches; (3) rate at which the system reacted to violative advertising; (4) prevalence of and oversight over claims regarding antidepressant efficacy and disease causality, and (5) costs for manufactures associated with violative advertising. Principal Findings Self-regulatory bodies identified numerous code breaches. Nonetheless, they failed to protect doctors from unreliable information on antidepressants, since as many as 247 of 722 (34%) advertisements breached the industry code. Self-regulatory bodies repeatedly failed to challenge inflated claims of antidepressant efficacy, lending evidence of lax oversight. On average, 15 weeks elapsed between printing and censure of a wrongful claim, and in 25% of cases 47 weeks or more elapsed. Industry paid roughly €108000 in fines for violative advertising, adding an estimated additional average cost of 11% to each purchased violative advertisement, or amounting to as little as 0.009% of total antidepressant sales of around €1.2 billion. Conclusions Lax oversight, combined with lags in the system and low fines for violations, may explain the Swedish system’s failure to pressure companies into providing reliable antidepressants information. If these shortcomings prove to be consistent across self-regulatory settings, and if appropriate measures are not taken to amend shortcomings, many countries may want to reconsider the current balance between self-regulation, and legislative control with government oversight.

Intersectionality and risk for ischemic heart disease in Sweden: Categorical and anti-categorical approaches

Intersectionality theory can contribute to epidemiology and public health by furthering understanding of power dynamics driving production of health disparities, and increasing knowledge about heterogeneities within, and overlap between, social categories. Drawing on McCall, we relate the first of these potential contributions to categorical intersectionality and the second to anti-categorical intersectionality. Both approaches are used in study of risk of ischemic heart disease (IHD), based on register data on 3.6 million adults residing in Sweden by 2010, followed for three years. Categorical intersectionality is here coupled with between-group differences in average risk calculation, as we use intersectional categorizations while estimating odds ratios through logistic regressions. The anti-categorical approach is operationalized through measurement of discriminatory accuracy (DA), i.e., capacity to accurately categorize individuals with or without a certain outcome, through computation of the area under the curve (AUC). Our results show substantial differences in average risk between intersectional groupings. The DA of social categorizations is found to be low, however, due to outcome variability within and overlap between categories. We argue that measures of DA should be used for proper interpretation of differences in average risk between social (or any other) categories. Tension between average between-group risk and the DA of categorizations, which can be related to categorical and anti-categorical intersectional analyses, should be made explicit and discussed to a larger degree in epidemiology and public health.

Complaints, Complainants, and Rulings Regarding Drug Promotion in the United Kingdom and Sweden 2004–2012: A Quantitative and Qualitative Study of Pharmaceutical Industry Self-Regulation

Background In many European countries, medicines promotion is governed by voluntary codes of practice administered by the pharmaceutical industry under its own system of self-regulation. Involvement of industry organizations in policing promotion has been proposed to deter illicit conduct, but few detailed studies on self-regulation have been carried out to date. The objective of this study was to examine the evidence for promotion and self-regulation in the UK and Sweden, two countries frequently cited as examples of effective self-regulation. Methods and Findings We performed a qualitative content analysis of documents outlining the constitutions and procedures of these two systems. We also gathered data from self-regulatory bodies on complaints, complainants, and rulings for the period 2004–2012. The qualitative analysis revealed similarities and differences between the countries. For example, self-regulatory bodies in both countries are required to actively monitor promotional items and impose sanctions on violating companies, but the range of sanctions is greater in the UK where companies may, for instance, be audited or publicly reprimanded. In total, Swedish and UK bodies ruled that 536 and 597 cases, respectively, were in breach, equating to an average of more than one case/week for each country. In Sweden, 430 (47%) complaints resulted from active monitoring, compared with only two complaints (0.2%) in the UK. In both countries, a majority of violations concerned misleading promotion. Charges incurred on companies averaged €447,000 and €765,000 per year in Sweden and the UK, respectively, equivalent to about 0.014% and 0.0051% of annual sales revenues, respectively. One hundred cases in the UK (17% of total cases in breach) and 101 (19%) in Sweden were highlighted as particularly serious. A total of 46 companies were ruled in breach of code for a serious offence at least once in the two countries combined (n = 36 in the UK; n = 27 in Sweden); seven companies were in serious violation more than ten times each. A qualitative content analysis of serious violations pertaining to diabetes drugs (UK, n = 15; Sweden, n = 6; 10% of serious violations) and urologics (UK, n = 6; Sweden, n = 13; 9%) revealed various types of violations: misleading claims (n = 23; 58%); failure to comply with undertakings (n = 9; 23%); pre-licensing (n = 7; 18%) or off-label promotion (n = 2; 5%); and promotion of prescription drugs to the public (n = 6; 15%). Violations that go undetected or unpunished by self-regulatory bodies are the main limitation of this study, since they are likely to lead to an underestimate of industry misconduct. Conclusions The prevalence and severity of breaches testifies to a discrepancy between the ethical standard codified in industry Codes of Conduct and the actual conduct of the industry. We discuss regulatory reforms that may improve the quality of medicines information, such as pre-vetting and intensified active monitoring of promotion, along with larger fines, and giving greater publicity to rulings. But despite the importance of improving regulatory arrangements in an attempt to ensure unbiased medicines information, such efforts alone are insufficient because simply improving oversight and increasing penalties fail to address additional layers of industry bias.

Questioning the discriminatory accuracy of broad migrant categories in public health: self-rated health in Sweden

Background: Differences between natives and migrants in average risk for poor self-rated health (SRH) are well documented, which has lent support to proposals for interventions targeting disadvantaged minority groups. However, such proposals are based on measures of association that neglect individual heterogeneity around group averages and thereby the discriminatory accuracy (DA) of the categories used (i.e. their ability to discriminate the individuals with poor and good SRH, respectively). Therefore, applying DA measures rather than only measures of association our study revisits the value of broad native and migrant categorizations for predicting SRH. Design, setting and participants: We analyzed 27 723 individuals aged 18–80 who responded to a 2008 Swedish public health survey. We performed logistic regressions to estimate odds ratios (ORs), predicted risks and the area under the receiver operating characteristic curve (AU-ROC) as a measure of epidemiological DA. Results: Being born abroad was associated with higher odds of poor SRH (OR = 1.75), but the AU-ROC of this variable only added 0.02 units to the AU-ROC for age alone (from 0.53 to 0.55). The AU-ROC increased, but remained unsatisfactorily low (0.62), when available social and demographic variables were included. Conclusions: Our results question the use of broad native/migrant categorizations as instruments for forecasting individual SRH. Such simple categorizations have a very low DA and should be abandoned in public health practice. Measures of association and DA should be reported together whenever an intervention is being considered, especially in the area of ethnicity, migration and health.

Rho-guanine nucleotide exchange factors during development: Force is nothing without control

The development of multicellular organisms is associated with extensive rearrangements of tissues and cell sheets. The driving force for these rearrangements is generated mostly by the actin cytoskeleton. In order to permit the reproducible development of a specific body plan, dynamic reorganization of the actin cytoskeleton must be precisely coordinated in space and time. GTP-exchange factors that activate small GTPases of the Rho family play an important role in this process. Here we review the role of this class of cytoskeletal regulators during important developmental processes such as epithelial morphogenesis, cytokinesis, cell migration, cell polarity, neuronal growth cone extension and phagocytosis in different model systems.

Pharmaceutical Industry Off-label Promotion and Self-regulation: A Document Analysis of Off-label Promotion Rulings by the United Kingdom Prescription Medicines Code of Practice Authority 2003-2012

Background European Union law prohibits companies from marketing drugs off-label. In the United Kingdom—as in some other European countries, but unlike the United States—industry self-regulatory bodies are tasked with supervising compliance with marketing rules. The objectives of this study were to (1) characterize off-label promotion rulings in the UK compared to the whistleblower-initiated cases in the US and (2) shed light on the UK self-regulatory mechanism for detecting, deterring, and sanctioning off-label promotion. Methods and Findings We conducted structured reviews of rulings by the UK self-regulatory authority, the Prescription Medicines Code of Practice Authority (PMCPA), between 2003 and 2012. There were 74 off-label promotion rulings involving 43 companies and 65 drugs. Nineteen companies were ruled in breach more than once, and ten companies were ruled in breach three or more times over the 10-y period. Drawing on a typology previously developed to analyse US whistleblower complaints, we coded and analysed the apparent strategic goals of each off-label marketing scheme and the practices consistent with those alleged goals. 50% of rulings cited efforts to expand drug use to unapproved indications, and 39% and 38% cited efforts to expand beyond approved disease entities and dosing strategies, respectively. The most frequently described promotional tactic was attempts to influence prescribers (n = 72, 97%), using print material (70/72, 97%), for example, advertisements (21/70, 30%). Although rulings cited prescribers as the prime target of off-label promotion, competing companies lodged the majority of complaints (prescriber: n = 16, 22%, versus companies: n = 42, 57%). Unlike US whistleblower complaints, few UK rulings described practices targeting consumers (n = 3, 4%), payers (n = 2, 3%), or company staff (n = 2, 3%). Eight UK rulings (11%) pertaining to six drugs described promotion of the same drug for the same off-label use as was alleged by whistleblowers in the US. However, while the UK cases typically related to only one or a few claims made in printed material, several complaints in the US alleged multifaceted and covert marketing activities. Because this study is limited to PMCPA rulings and whistleblower-initiated federal cases, it may offer a partial view of exposed off-label marketing. Conclusion The UK self-regulatory system for exposing marketing violations relies largely on complaints from company outsiders, which may explain why most off-label promotion rulings relate to plainly visible promotional activities such as advertising. This contrasts with the US, where Department of Justice investigations and whistleblower testimony have alleged complex off-label marketing campaigns that remain concealed to company outsiders. UK authorities should consider introducing increased incentives and protections for whistleblowers combined with US-style governmental investigations and meaningful sanctions. UK prescribers should be attentive to, and increasingly report, off-label promotion.

Measures of discriminatory accuracy and categorizations in public health: a response to Allan Krasnik’s editorial

In a recent Editorial,1 Allan Krasnik gives an excellent commentary to our article questioning the discriminatory accuracy of broad migrant categories in Public Health.2 Krasnik embraces our opinions and also arrives to a balanced approach for future research. He agrees with us on the perils of using measures of association (e.g. odds ratios, relative risks and risk differences) alone especially when they are based on inappropriately specified categorizations, like many ethnic categorizations are. Besides concerns on causal validity, measures of association do not inform on the individual heterogeneity of responses around the average and, thereby, provide insufficient information on the distribution of the health …

Does Maternal Country of Birth Matter for Understanding Offspring’s Birthweight? A Multilevel Analysis of Individual Heterogeneity in Sweden

Background Many public health and epidemiological studies have found differences between populations (e.g. maternal countries of birth) in average values of a health indicator (e.g. mean offspring birthweight). However, the approach based solely on population-level averages compromises our understanding of variability in individuals’ health around the averages. If this variability is high, the exclusive study of averages may give misleading information. This idea is relevant when investigating country of birth differences in health. Methods and Results To exemplify this concept, we use information from the Swedish Medical Birth Register (2002–2010) and apply multilevel regression analysis of birthweight, with babies (n = 811,329) at the first, mothers (n = 571,876) at the second, and maternal countries of birth (n = 109) at the third level. We disentangle offspring, maternal and maternal country of birth components of the total offspring heterogeneity in birthweight for babies born within the normal timespan (37–42 weeks). We found that of such birthweight variation about 50% was at the baby level, 47% at the maternal level and only 3% at the maternal countries of birth level. Conclusion In spite of seemingly large differences in average birthweight among maternal countries of birth (range 3290–3677g), knowledge of the maternal country of birth does not provide accurate information for ascertaining individual offspring birthweight because of the high inter-offspring heterogeneity around country averages. Our study exemplifies the need for a better understanding of individual health diversity for which group averages may provide insufficient and even misleading information. The analytical approach we outline is therefore relevant to investigations of country of birth (and ethnic) differences in health in general.