Strange Bedfellows: Native American Tribes, Big Pharma, and the Legitimacy of Their Alliance

Lost in the cacophony surrounding the debate about high drug prices is the fundamental principle that pharmaceutical innovation will not occur without the prospect of outsized returns enabled through market exclusivity. Biopharmaceutical patents are currently under siege, subject to challenge both in inter partes review (“IPR”) proceedings and in Hatch-Waxman actions. These twin assaults threaten to eliminate the incentives necessary for biotechnological innovation—particularly for discoveries made upstream in the innovation pipeline—thus imperiling the development of new drug therapies. But a fascinating solution has emerged: invoking tribal immunity to shield pharmaceutical patents from IPR before the Patent Trial and Appeal Board (“PTAB”). This serves two critically important objectives: promoting tribal self-sufficiency, and encouraging investment in life-saving and life-improving new drugs. Contractual partnerships between Native American tribes and pharmaceutical companies not only provide the tribes with a steady stream of royalty revenue, but also insulate biopharmaceutical patents from challenge in IPR proceedings through the invocation of long-established principles of tribal sovereign immunity. This Note is the first piece of scholarship to comprehensively analyze, and advocate for, the right to invoke tribal sovereign immunity in IPR proceedings

Effect of a crack emanating from notch on a composite pipe subjected to buckling

New pipelines made with composite materials have to be well-designed for better mechanical performances. Recommendations for sizing stratified pipes have been proposedfor different combinations of loads. In this context, our paper focus on buckling on laminated composite pipes, using numerical simulation. As a first part, we study free-defect pipes buckling for different pipe diameters, wall thicknesses and fibers orientation. In a second part, we evaluate the influence of defects (notches and crack due to notches), their parameters (size, orientation) and mechanical constraints (pipe under pressure, boundary conditions) on the structure. Results show a strong dependence of the size of the notch to the stability of the structure, amplified by the fibers orientation. Thus, for fibers oriented at an angle close to 20°, pipes manufacturing under these conditions show a particular strength of the structure. The crack length (independently on its orientation) seems to have no significant effect on the buckling factor and therefore the structure integrity, for transverse-orientated fibers and while their orientation go beyond 40°. The main variations are observed when fibers orientation is in the range from a few degrees up to 40°. Results are and discussed according the orientation of crack and fibers

Effet du flambage sur les parois d'un réservoir de stockage

Les structures minces de type coques métalliques sont particulièrement sensibles au flambage ou instabilité géométrique. Leur dimensionnement s'opère en ayant recours à des règles simplifiées, cette approche est généralement conservative. En effet ces structures sont très sensibles à la moindre imperfection de forme (défauts géométriques initiaux). Le dimensionnement s'appuie en général sur la connaissance de l'état initial réel ou supposé. Or cette configuration évolue dans le temps, on constate généralement l'adjonction de nouveaux défauts de forme dus au fonctionnement (charges accidentelles, fluage) mais aussi à des pertes de matière localisées dans les zones corrodées. La prise en compte de ces divers dommages conduits généralement à une perte de capacité portante. Afin de préserver le potentiel de charge de la structure, il est alors nécessaire de trouver un autre matériau. Dans notre étude nous envisageons de remplacer le matériau utilisé pour les réservoirs trouvés dans l'entreprise SONATRACH par un matériau composite à base de fibre de carbone ou de verre. 6 à 12 couches de composite sont simplement collées. Une recherche est consacrée à l'étude du flambage de coques multicouches soumises à un déplacement imposé, nous a permis de dégager les paramètres déterminants et ceux dont l'effet est moindre. Pour l'ensemble des résultats obtenus, on constate que le carbone époxy T700E est le plus résistant, l'augmentation du nombre de couche augmente la résistance du réservoir

Effect of a crack emanating from notch on a composite pipe subjected to buckling

New pipelines made with composite materials have to be well-designed for better mechanical performances. Recommendations for sizing stratified pipes have been proposedfor different combinations of loads. In this context, our paper focus on buckling on laminated composite pipes, using numerical simulation. As a first part, we study free-defect pipes buckling for different pipe diameters, wall thicknesses and fibers orientation. In a second part, we evaluate the influence of defects (notches and crack due to notches), their parameters (size, orientation) and mechanical constraints (pipe under pressure, boundary conditions) on the structure. Results show a strong dependence of the size of the notch to the stability of the structure, amplified by the fibers orientation. Thus, for fibers oriented at an angle close to 20°, pipes manufacturing under these conditions show a particular strength of the structure. The crack length (independently on its orientation) seems to have no significant effect on the buckling factor and therefore the structure integrity, for transverse-orientated fibers and while their orientation go beyond 40°. The main variations are observed when fibers orientation is in the range from a few degrees up to 40°. Results are and discussed according the orientation of crack and fibers

Acute Schistosoma mansoni Infection Increases Susceptibility to Systemic SHIV Clade C Infection in Rhesus Macaques after Mucosal Virus Exposure

To test the hypothesis that infection with helmiths may increase host susceptibility to infection with HIV-1, we quantified the amount of a clade C simian-human immunodeficiency virus needed to infect rhesus macaques that had acute Schistosoma mansoni infections. Compared to control animals exposed to virus alone, monkeys with schistosomiasis required exposure to 17-fold lower levels of virus to become infected. The schistosome-infected monkeys also had significantly higher levels of initial virus replication and loss of a certain subset of memory T cells, both predictors of a more rapid progression to immune dysfunction. These results suggest that worm infections may increase the risk of becoming infected with HIV-1 among individuals with viral exposures. Furthermore, they support the idea that control programs for schistosomiasis and perhaps other parasitic worm infections may also be useful in helping to reduce the spread of HIV/AIDS in developing countries where helminths are endemic

Truncated forms of human and simian immunodeficiency virus in infected individuals and rhesus macaques are unique or rare quasispecies

AbstractTruncated proviruses of variable sizes are present in peripheral blood mononuclear cells (PBMC) of human immunodeficiency virus type 1 (HIV-1)-infected persons and simian immunodeficiency virus (SIV)-infected rhesus macaques. Here, we investigated whether the highly deleted HIV and SIV proviruses are present in infected organisms as multiple copies or whether each truncated provirus is unique. Using end-point dilution, multiple long-distance (LD) DNA PCR assays were run in parallel using DNA extracted from PBMC of seropositive, treatment-naive persons and from lymph nodes of a rhesus monkey inoculated with cloned, full-length SIVmac239 DNA. The PCR products were titrated and mapped. Most truncated proviruses were present in the DNA samples tested as single, nonintegrated molecules that differed from one another in size and/or nucleotide sequence. These results indicate that truncated primate lentiviral sequences found in infected tissues are unique or rare quasispecies that do not replicate significantly

Schistosoma mansoni Enhances Host Susceptibility to Mucosal but Not Intravenous Challenge by R5 Clade C SHIV

Parasitic infections have been postulated to increase host susceptibility to HIV-1. We previously demonstrated that rhesus monkeys with active schistosomiasis were significantly more likely to become systemically infected after intrarectal exposure to an R5-tropic clade C simian-human immunodeficiency virus then were parasite-free control animals. However, we could not address whether parasites exert their effect at the mucosal level or systemically. To address the latter possibility, we measured the virus doses needed to achieve systemic infection after intravenous exposure of parasite-free or parasite-positive monkeys using the identical virus stock. None of the viral parameters tested in these two groups of monkeys were statistically significantly different. These results suggest that schistosomiasis modulates susceptibility to immunodeficiency virus acquisition predominantly at the mucosal level. Treatment for parasitic infections in populations at higher risk for HIV-1 acquisition could represent a cost-effective approach to slow the spread of HIV-1, which is predominantly transmitted through mucosal routes

SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys

Background: Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. SHIV challenges allow assessment of anti-HIV-1 envelope responses in primates. As such, SHIVs should mimic natural HIV-1 infection in humans and, to address the pandemic, encode HIV-1 Env components representing major viral subtypes worldwide. Results: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype. The parental infectious proviral clone, SHIV-1157i, was rapidly passaged through five rhesus monkeys. After AIDS developed in the first animal at week 123 post-inoculation, infected blood was infused into a sixth monkey. Virus reisolated at this late stage was still exclusively R5 tropic and mucosally transmissible. Here we describe the long-term follow-up of this initial cohort of six monkeys. Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123–270 weeks post-exposure. Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis. Conclusion: These data document the disease progression induced by the first mucosally transmissible, pathogenic R5 non-clade B SHIV and suggest that SHIV-1157i-derived viruses, including the late-stage, highly replication-competent SHIV-1157ipd3N4 previously described (Song et al., 2006), display biological characteristics that mirror those of HIV-1 clade C and support their expanded use for AIDS vaccine studies in nonhuman primates

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease