Turing and the Trans-Pacific Partnership: Intellectual Property, Public Health, and Access to Essential Medicines

A recent controversy in the United States over drug pricing by Turing Pharmaceuticals AG has raised larger issues in respect of intellectual property, access to medicines, and the Trans-Pacific Partnership (TPP). In August 2015, Turing Pharmaceuticals AG – a private biopharmaceutical company with offices in New York, the United States, and Zug, Switzerland - acquired the exclusive marketing rights to Daraprim in the United States from Impax Laboratories Incorporated. Martin Shkreli, Turing’s Founder and Chief Executive Officer, maintained: “The acquisition of Daraprim and our toxoplasmosis research program are significant steps along Turing’s path of bringing novel medications to patients with serious disorders, some of whom often go undiagnosed and untreated.” He emphasised: “We intend to invest in the development of new drug candidates that we hope will yield an even better clinical profile, and also plan to launch an educational effort to help raise awareness and improve diagnosis for patients with toxoplasmosis.” In September 2015, there was much public controversy over the decision of Martin Shkreli to raise the price of a 62 year old drug, Daraprim, from $US13.50 to $US750 a pill. The drug is particularly useful in respect to the treatment and prevention of malaria, and in the treatment of infections in individuals with HIV/AIDS. Daraprim is listed on the World Health Organization’s (WHO) List of Essential Medicines. In the face of much criticism, Martin Shkreli has said that he will reduce the price of Daraprim. He observed: “We've agreed to lower the price on Daraprim to a point that is more affordable and is able to allow the company to make a profit, but a very small profit.” He maintained: “We think these changes will be welcomed.” However, he has been vague and ambiguous about the nature of the commitment. Notably, the lobby group, Pharmaceutical Research and Manufacturers of America (PhARMA), disassociated itself from the claims of Turing Pharmaceuticals. The group said: “PhRMA members have a long history of drug discovery and innovation that has led to increased longevity and improved lives for millions of patients.” The group noted: “Turing Pharmaceutical is not a member of PhRMA and we do not embrace either their recent actions or the conduct of their CEO.” The biotechnology peak body Biotechnology Industry Organization also sought to distance itself from Turing Pharmaceuticals. A hot topic: United States political debate about access to affordable medicines This controversy over Daraprim is unusual – given the age of drug concerned. Daraprim is not subject to patent protection. Nonetheless, there remains a monopoly in respect of the marketplace. Drug pricing is not an isolated problem. There have been many concerns about drug pricing – particularly in respect of essential medicines for HIV/AIDS, tuberculosis, and malaria. This recent controversy is part of a larger debate about access to affordable medicines. The dispute raises larger issues about healthcare, consumer rights, competition policy, and trade. The Daraprim controversy has provided impetus for law reform in the US. US Presidential Candidate Hillary Clinton commented: “Price gouging like this in this specialty drug market is outrageous.” In response to her comments, the Nasdaq Biotechnology Index fell sharply. Hillary Clinton has announced a prescription drug reform plan to protect consumers and promote innovation – while putting an end to profiteering. On her campaign site, she has emphasised that “affordable healthcare is a basic human right.” Her rival progressive candidate, Bernie Sanders, was also concerned about the price hike. He wrote a letter to Martin Shkreli, complaining about the price increase for the drug Daraprim. Sanders said: “The enormous, overnight price increase for Daraprim is just the latest in a long list of skyrocketing price increases for certain critical medications.” He has pushed for reforms to intellectual property to make medicines affordable. The TPP and intellectual property The Daraprim controversy and political debate raises further issues about the design of the TPP. The dispute highlights the dangers of extending the rights of pharmaceutical drug companies under intellectual property, investor-state dispute settlement, and drug administration. Recently, the civil society group Knowledge Ecology International published a leaked draft of the Intellectual Property Chapter of the TPP. Knowledge Ecology International Director, James Love, was concerned the text revealed that the US “continues to be the most aggressive supporter of expanded intellectual property rights for drug companies.” He was concerned that “the proposals contained in the TPP will harm consumers and in some cases block innovation.” James Love feared: “In countless ways, the Obama Administration has sought to expand and extend drug monopolies and raise drug prices.” He maintained: “The astonishing collection of proposals pandering to big drug companies make more difficult the task of ensuring access to drugs for the treatment of cancer and other diseases and conditions.” Love called for a different approach to intellectual property and trade: “Rather than focusing on more intellectual property rights for drug companies, and a death-inducing spiral of higher prices and access barriers, the trade agreement could seek new norms to expand the funding of medical research and development (R&D) as a public good, an area where the US has an admirable track record, such as the public funding of research at the National Institutes of Health (NIH) and other federal agencies.” In addition, there has been much concern about the Investment Chapter of the TPP. The investor-state dispute settlement regime would enable foreign investors to challenge government policy making, which affected their investments. In the context of healthcare, there is a worry that pharmaceutical drug companies will deploy their investor rights to challenge public health measures – such as, for instance, initiatives to curb drug pricing and profiteering. Such concerns are not merely theoretical. Eli Lilly has brought an investor action against the Canadian Government over the rejection of its drug patents under the investor-state dispute settlement regime of the North American Free Trade Agreement (NAFTA). The Health Annex to the TPP also raises worries that pharmaceutical drug companies will able to object to regulatory procedures in respect of healthcare. It is disappointing that the TPP – in the leaks that we have seen – has only limited recognition of the importance of access to essential medicines. There is a need to ensure that there are proper safeguards to provide access to essential medicines – particularly in respect of HIV/AIDs, malaria, and tuberculosis. Moreover, there must be protection against drug profiteering and price gouging in any trade agreement. There should be strong measures against the abuse of intellectual property rights. The dispute over Turing Pharmaceuticals AG and Daraprim is an important cautionary warning in respect of some of the dangers present in the secret negotiations in respect of the TPP. There is a need to preserve consumer rights, competition policy, and public health in trade negotiations over an agreement covering the Pacific Rim.

Applying an equity lens to tobacco-control policies and their uptake in six western-european countries

We identified policies that may be effective in reducing smoking among socioeconomically disadvantaged groups, and examined trends in their level of application between 1985 and 2000 in six western-European countries (Sweden, Finland, the United Kingdom, the Netherlands, Germany, and Spain). We located studies from literature searches in major databases, and acquired policy data from international data banks and questionnaires distributed to tobacco policy organisations/researchers. Advertising bans, smoking bans in workplaces, removing barriers to smoking cessation therapies, and increasing the cost of cigarettes have the potential to reduce socioeconomic inequalities in smoking. Between 1985 and 2000, tobacco control policies in most countries have become more targeted to decrease the smoking behaviour of low-socioeconomic groups. Despite this, many national tobacco-control strategies in western-European countries still fall short of a comprehensive policy approach to addressing smoking inequalities.

Manufacturing challenges with fabrication of large size mechanical harmonic drives

In truck manufacturing, the exhaust and air inlet pipes are specialized equipment that requires highly skilled, heavy machinery and small batch production methods. This paper describes a project to develop the computer numerically controlled (CNC) pipe bending process for a truck component manufacturer. The company supplies a huge range of heavy duty truck parts to the domestic market and is a significant supplier in Australia. The company has been using traditional methods of machine assisted manual pipe bending techniques. In a drive of continuous improvement, the company has acquired a pre-owned CNC bending machine capable of bending pipes automatically up to 25 bends. However, due to process mismatch, this machine is only used for single bending operation. The researchers studied the bending system and changed the manufacturing process. Using an example exhaust pipe as the benchmark, a significant drop of manufacturing lead time from 70 minutes to 40 minutes for each pipe was demonstrated. There was also a decrease of material cost due to the multiple bends part in one piece without cutting excessive materials for each single bend like it used to be.

Trust and strong ties in the selection and evaluation of business advisors by small firms

Principal Topic A small firm is unlikely to possess internally the full range of knowledge and skills that it requires or could benefit from for the development of its business. The ability to acquire suitable external expertise - defined as knowledge or competence that is rare in the firm and acquired from the outside - when needed thus becomes a competitive factor in itself. Access to external expertise enables the firm to focus on its core competencies and removes the necessity to internalize every skill and competence. However, research on how small firms access external expertise is still scarce. The present study contributes to this under-developed discussion by analysing the role of trust and strong ties in the small firm's selection and evaluation of sources of external expertise (henceforth referred to as the 'business advisor' or 'advisor'). Granovetter (1973, 1361) defines the strength of a network tie as 'a (probably linear) combination of the amount of time, the emotional intensity, the intimacy (mutual confiding) and the reciprocal services which characterize the tie'. Strong ties in the context of the present investigation refer to sources of external expertise who are well known to the owner-manager, and who may be either informal (e.g., family, friends) or professional advisors (e.g., consultants, enterprise support officers, accountants or solicitors). Previous research has suggested that strong and weak ties have different fortes and the choice of business advisors could thus be critical to business performance) While previous research results suggest that small businesses favour previously well known business advisors, prior studies have also pointed out that an excessive reliance on a network of well known actors might hamper business development, as the range of expertise available through strong ties is limited. But are owner-managers of small businesses aware of this limitation and does it matter to them? Or does working with a well-known advisor compensate for it? Hence, our research model first examines the impact of the strength of tie on the business advisor's perceived performance. Next, we ask what encourages a small business owner-manager to seek advice from a strong tie. A recent exploratory study by Welter and Kautonen (2005) drew attention to the central role of trust in this context. However, while their study found support for the general proposition that trust plays an important role in the choice of advisors, how trust and its different dimensions actually affect this choice remained ambiguous. The present paper develops this discussion by considering the impact of the different dimensions of perceived trustworthiness, defined as benevolence, integrity and ability, on the strength of tie. Further, we suggest that the dimensions of perceived trustworthiness relevant in the choice of a strong tie vary between professional and informal advisors. Methodology/Key Propositions Our propositions are examined empirically based on survey data comprising 153 Finnish small businesses. The data are analysed utilizing the partial least squares (PLS) approach to structural equation modelling with SmartPLS 2.0. Being non-parametric, the PLS algorithm is particularly well-suited to analysing small datasets with non-normally distributed variables. Results and Implications The path model shows that the stronger the tie, the more positively the advisor's performance is perceived. Hypothesis 1, that strong ties will be associated with higher perceptions of performance is clearly supported. Benevolence is clearly the most significant predictor of the choice of a strong tie for external expertise. While ability also reaches a moderate level of statistical significance, integrity does not have a statistically significant impact on the choice of a strong tie. Hence, we found support for two out of three independent variables included in Hypothesis 2. Path coefficients differed between the professional and informal advisor subsamples. The results of the exploratory group comparison show that Hypothesis 3a regarding ability being associated with strong ties more pronouncedly when choosing a professional advisor was not supported. Hypothesis 3b arguing that benevolence is more strongly associated with strong ties in the context of choosing an informal advisor received some support because the path coefficient in the informal advisor subsample was much larger than in the professional advisor subsample. Hypothesis 3c postulating that integrity would be more strongly associated with strong ties in the choice of a professional advisor was supported. Integrity is the most important dimension of trustworthiness in this context. However, integrity is of no concern, or even negative, when using strong ties to choose an informal advisor. The findings of this study have practical relevance to the enterprise support community. First of all, given that the strength of tie has a significant positive impact on the advisor's perceived performance, this implies that small business owners appreciate working with advisors in long-term relationships. Therefore, advisors are well advised to invest into relationship building and maintenance in their work with small firms. Secondly, the results show that, especially in the context of professional advisors, the advisor's perceived integrity and benevolence weigh more than ability. This again emphasizes the need to invest time and effort into building a personal relationship with the owner-manager, rather than merely maintaining a professional image and credentials. Finally, this study demonstrates that the dimensions of perceived trustworthiness are orthogonal with different effects on the strength of tie and ultimately perceived performance. This means that entrepreneurs and advisors should consider the specific dimensions of ability, benevolence and integrity, rather than rely on general perceptions of trustworthiness in their advice relationships.

Suicidal ideation, suicide attempts, and HIV infection

A cross-sectional study was performed to investigate the prevalence and predictors of suicidal ideation and past suicide attempt in an Australian sample of human imumunodeficiency virus (HIV)-positive and HIV-negative homosexual and bisexual men. Sixty-five HIV-negative and 164 HIV-positive men participated. A suicidal ideation score was derived from using five items selected from the Beck Depression Inventory and the General Health Questionnaire (28-item version). Lifetime and current prevalence rates of psychiatric disorder were evaluated with the Diagnostic Interview Schedule Version-III-R. The HIV-positive (Centers for Disease Control and Prevention [CDC] Stage IV) men (n=85) had significantly higher total suicidal ideation scores than the asymptomatic HIV-positive men (CDC Stage II/III) (n=79) and the HIV-negative men. High rates of past suicide attempt were detected in the HIV-negative (29%) and HIV-positive men (21%). Factors associated with suicidal ideation included being HIV-positive, the presence of current psychiatric disorder, higher neuroticism scores, external locus of control, and current unemployment. In the HIV-positive group analyzed separately, higher suicidal ideation was discriminated by the adjustment to HIV diagnosis (greater hopelessness and lower fighting spirit), disease factors (greater number of current acquired immunodeficiency syndrome [AIDS]-related conditions), and background variables (neuroticism). Significant predictors of a past attempted suicide were a positive lifetime history of psychiatric disorder (particularly depression diagnoses), a lifetime history of injection drug use, and a family history of suicide attempts. The findings indicate increased levels of suicidal ideation in symptomatic HIV-positive men and highlight the role that multiple psychosocial factors associated with suicidal ideation and attempted suicide play in this population.

Citizen journalism and everyday life : A case study of Germany’s myHeimat.de

Much recent research into citizen journalism has focussed on its role in political debate and deliberation. Such research examines important questions about citizen participation in democratic processes – however, it perhaps places undue focus on only one area of journalistic coverage, and presents a challenge which only a small number of citizen journalism projects can realistically hope to meet. A greater opportunity for broad-based citizen involvement in journalistic activities may lie outside of politics, in the coverage of everyday community life. A leading exponent of this approach is the German-based citizen journalism Website myHeimat.de, which provides a nationwide platform for participants to contribute reports about events in their community. myHeimat takes a hyperlocal approach but also allows for content aggregation on specific topics across multiple local communities; Hannover-based newspaper publishing house Madsack has recently acquired a stake in the project. Drawing on extensive interviews with myHeimat CEO Martin Huber and Madsack newspaper editors Peter Taubald and Clemens Wlokas during October 2008, this paper analyses the myHeimat project and examines its applicability beyond rural and regional areas in Germany; it investigates the question of what role citizen journalism may play beyond the political realm.

Towards a Rule-based matrix for evaluating distress mechanisms in bridges

One of the key issues facing public asset owners is the decision of refurbishing aged built assets. This decision requires an assessment of the “remaining service life” of the key components in a building. The remaining service life is significantly dependent upon the existing condition of the asset and future degradation patterns considering durability and functional obsolescence. Recently developed methods on Residual Service Life modelling, require sophisticated data that are not readily available. Most of the data available are in the form of reports prior to undertaking major repairs or in the form of sessional audit reports. Valuable information from these available sources can serve as bench marks for estimating the reference service life. The authors have acquired similar informations from a public asset building in Melbourne. Using these informations, the residual service life of a case study building façade has been estimated in this paper based on state-of-the-art approaches. These estimations have been evaluated against expert opinion. Though the results are encouraging it is clear that the state-of-the-art methodologies can only provide meaningful estimates provided the level and quality of data are available. This investigation resulted in the development of a new framework for maintenance that integrates the condition assessment procedures and factors influencing residual service life

The economic rationale for infection control in Australian hospitals

The objective of the present study was to predict the economic consequences of healthcare-acquired infections arising among admissions to Australian acute care hospitals. A quantitative algorithm informed by epidemiological and economic data was developed. All acute care hospitals in Australia were included in the study and the participants included all admissions to general medical and general surgical specialties. The main outcome measures were the numbers of cases of healthcare-acquired infection and bed days lost annually. It was estimated that there are 175 153 (95% credible interval 155 911 : 195 168) cases of healthcare-acquired infection among admissions to Australian hospitals annually, and the extra stay in hospital to treat symptoms accounts for 854 289 bed days (95% credible interval 645 091 : 1 096 244). If rates were reduced by 1%, then 150 158 bed days would be released for alternative uses. This would allow ~38 500 new admissions. Healthcare-acquired infections in patients cause bed blocks in Australian hospitals. The cost-effectiveness of hospital services might be improved by allocating more resources to infection control, releasing beds and allowing new admissions. There exists an opportunity to improve the efficiency of the Australian health care system.

Integrating concrete and virtual materials in an elementary mathematics classroom : a case study of success with fractions

This paper describes an approach to introducing fraction concepts using generic software tools such as Microsoft Office's PowerPoint to create "virtual" materials for mathematics teaching and learning. This approach replicates existing concrete materials and integrates virtual materials with current non-computer methods of teaching primary students about fractions. The paper reports a case study of a 12-year-old student, Frank, who had an extremely limited understanding of fractions. Frank also lacked motivation for learning mathematics in general and interacted with his peers in a negative way during mathematics lessons. In just one classroom session involving the seamless integration of off-computer and on-computer activities, Frank acquired a basic understanding of simple common equivalent fractions. Further, he was observed as the session progressed to be an enthusiastic learner who offered to share his learning with his peers. The study's "virtual replication" approach for fractions involves the manipulation of concrete materials (folding paper regions) alongside the manipulation of their virtual equivalent (shading screen regions). As researchers have pointed out, the emergence of new technologies does not mean old technologies become redundant. Learning technologies have not replaced print and oral language or basic mathematical understanding. Instead, they are modifying, reshaping, and blending the ways in which humankind speaks, reads, writes, and works mathematically. Constructivist theories of learning and teaching argue that mathematics understanding is developed from concrete to pictorial to abstract and that, ultimately, mathematics learning and teaching is about refinement and expression of ideas and concepts. Therefore, by seamlessly integrating the use of concrete materials and virtual materials generated by computer software applications, an opportunity arises to enhance the teaching and learning value of both materials.

Fusion of in-vehicle sensor data to develop Intelligent Driver Training System (IDTS)

The over represented number of novice drivers involved in crashes is alarming. Driver training is one of the interventions aimed at mitigating the number of crashes that involve young drivers. To our knowledge, Advanced Driver Assistance Systems (ADAS) have never been comprehensively used in designing an intelligent driver training system. Currently, there is a need to develop and evaluate ADAS that could assess driving competencies. The aim is to develop an unsupervised system called Intelligent Driver Training System (IDTS) that analyzes crash risks in a given driving situation. In order to design a comprehensive IDTS, data is collected from the Driver, Vehicle and Environment (DVE), synchronized and analyzed. The first implementation phase of this intelligent driver training system deals with synchronizing multiple variables acquired from DVE. RTMaps is used to collect and synchronize data like GPS, vehicle dynamics and driver head movement. After the data synchronization, maneuvers are segmented out as right turn, left turn and overtake. Each maneuver is composed of several individual tasks that are necessary to be performed in a sequential manner. This paper focuses on turn maneuvers. Some of the tasks required in the analysis of ‘turn’ maneuver are: detect the start and end of the turn, detect the indicator status change, check if the indicator was turned on within a safe distance and check the lane keeping during the turn maneuver. This paper proposes a fusion and analysis of heterogeneous data, mainly involved in driving, to determine the risk factor of particular maneuvers within the drive. It also explains the segmentation and risk analysis of the turn maneuver in a drive.

Further evidence of a relationship between explaining, tracing and writing skills in introductory programming

This paper reports on a replication of earlier studies into a possible hierarchy of programming skills. In this study, the students from whom data was collected were at a university that had not provided data for earlier studies. Also, the students were taught the programming language Python, which had not been used in earlier studies. Thus this study serves as a test of whether the findings in the earlier studies were specific to certain institutions, student cohorts, and programming languages. Also, we used a non–parametric approach to the analysis, rather than the linear approach of earlier studies. Our results are consistent with the earlier studies. We found that students who cannot trace code usually cannot explain code, and also that students who tend to perform reasonably well at code writing tasks have also usually acquired the ability to both trace code and explain code.

Using a longitudinal model to estimate the effect of methicillin-resistant staphylococcus aureus infection on length of stay in an intensive care unit

Healthcare-associated methicillin-resistant Staphylococcus aureus(MRSA) infection may cause increased hospital stay or, sometimes, death. Quantifying this effect is complicated because it is a time-dependent exposure: infection may prolong hospital stay, while longer stays increase the risk of infection. We overcome these problems by using a multinomial longitudinal model for estimating the daily probability of death and discharge. We then extend the basic model to estimate how the effect of MRSA infection varies over time, and to quantify the number of excess ICU days due to infection. We find that infection decreases the relative risk of discharge (relative risk ratio = 0.68, 95% credible interval: 0.54, 0.82), but is only indirectly associated with increased mortality. An infection on the first day of admission resulted in a mean extra stay of 0.3 days (95% CI: 0.1, 0.5) for a patient with an APACHE II score of 10, and 1.2 days (95% CI: 0.5, 2.0) for a patient with an APACHE II score of 30. The decrease in the relative risk of discharge remained fairly constant with day of MRSA infection, but was slightly stronger closer to the start of infection. These results confirm the importance of MRSA infection in increasing ICU stay, but suggest that previous work may have systematically overestimated the effect size.

Increasing stochastic perturbations enhances acquisition and learning of complex sport movements

Traditionally, the aquisition of skills and sport movement has been characterised by numerous repetitions of presumed model movement pattern to be acquired by learners. This approach has been questioned by research identifying the presence of individualised movement patterns and the low probability of occurrence of two identical movements within and between individuals. In contrast, the differential learning approach claims advantage for incurring variability in the learning process by adding stochastic perturbations during practice. These ideas are exemplified by data from a high jump experiment which compared the effectiveness of classical and a differential training approach with pre-post test design. Results showed clear advantages for the group with additional stochastic perturbation during the aquisition phase in comparison to classically trained athletes. Analogies to similar phenomenological effects in the neurobiological literature are discussed.

Effect of female sex hormones on Chlamydia trachomatis growth and gene expression

Transmissible diseases are re-emerging as a global problem, with Sexually Transmitted Diseases (STDs) becoming endemic. Chlamydia trachomatis is the leading cause of bacterially-acquired STD worldwide, with the Australian cost of infection estimated at $90 - $160 million annually. Studies using animal models of genital tract Chlamydia infection suggested that the hormonal status of the genital tract epithelium at the time of exposure may influence the outcome of infection. Oral contraceptive use also increased the risk of contracting chlamydial infections compared to women not using contraception. Generally it was suggested that the outcome of chlamydial infection is determined in part by the hormonal status of the epithelium at the time of exposure. Using the human endolmetrial cell line ECC-1 this study investigated the effects of C. trachomatis serovar D infection, in conjunction with the female sex hormones, 17β-estradiol and progesterone, on chlamydial gene expression. While previous studies have examined the host response, this is the first study to examine C.trachomatis gene expression under different hormonal conditions. We have highlighted a basic model of C. trachomatis gene regulation in the presence of steroid hormones by identifying 60 genes that were regulated by addition of estradiol and/or progesterone. In addition, the third chapter of this thesis discussed and compared the significance of the current findings in the context of data from other research groups to improve our understanding of the molecular basis of chlamydial persistence under hormonal different conditions. In addition, this study analysed the effects of these female sex hormones and C. trachomatis Serovar D infection, on host susceptibility and bacterial growth. Our results clearly demonstrated that addition of steroid hormones not only had a great impact on the level of infectivity of epithelial cells with C.trachomatis serovar D, but also the morphology of chlamydial inclusions was affected by hormone supplementation.