Pricing in the Market for Anticancer Drugs

In 2011, Bristol-Myers Squibb set the price of its newly approved melanoma drug ipilimumab— brand name Yervoy—at $120,000 for a course of therapy. The drug was associated with an incremental increase in life expectancy of four months. Drugs like ipilimumab have fueled the perception that the launch prices of new anticancer drugs and other drugs in the so-called "specialty" pharmaceutical market have been increasing over time and that increases are unrelated to the magnitude of the expected health benefits. In this paper, we discuss the unique features of the market for anticancer drugs and assess trends in the launch prices for 58 anticancer drugs approved between 1995 and 2013 in the United States. We restrict attention to anticancer drugs because the use of median survival time as a primary outcome measure provides a common, objective scale for quantifying the incremental benefit of new products. We find that the average launch price of anticancer drugs, adjusted for inflation and health benefits, increased by 10 percent annually—or an average of$8,500 per year—from 1995 to 2013. We argue that the institutional features of the market for anticancer drugs enable manufacturers to set the prices of new products at or slightly above the prices of existing therapies, giving rise to an upward trend in launch prices. Government-mandated price discounts for certain classes of buyers may have also contributed to launch price increases as firms sought to offset the growth in the discount segment by setting higher prices for the remainder of the market

Carbon Monoxide Protects against Liver Failure through Nitric Oxide–induced Heme Oxygenase 1

Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor α–induced hepatocyte cell death in mice, we find that activation of nuclear factor κB and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection

Least Dependent Component Analysis Based on Mutual Information

We propose to use precise estimators of mutual information (MI) to find least dependent components in a linearly mixed signal. On the one hand this seems to lead to better blind source separation than with any other presently available algorithm. On the other hand it has the advantage, compared to other implementations of `independent' component analysis (ICA) some of which are based on crude approximations for MI, that the numerical values of the MI can be used for: (i) estimating residual dependencies between the output components; (ii) estimating the reliability of the output, by comparing the pairwise MIs with those of re-mixed components; (iii) clustering the output according to the residual interdependencies. For the MI estimator we use a recently proposed k-nearest neighbor based algorithm. For time sequences we combine this with delay embedding, in order to take into account non-trivial time correlations. After several tests with artificial data, we apply the resulting MILCA (Mutual Information based Least dependent Component Analysis) algorithm to a real-world dataset, the ECG of a pregnant woman. The software implementation of the MILCA algorithm is freely available at http://www.fz-juelich.de/nic/cs/softwareComment: 18 pages, 20 figures, Phys. Rev. E (in press

Hydrothermal venting in magma deserts : the ultraslow-spreading Gakkel and Southwest Indian Ridges

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 5 (2004): Q08002, doi:10.1029/2004GC000712.Detailed hydrothermal surveys over ridges with spreading rates of 50–150 mm/yr have found a linear relation between spreading rate and the spatial frequency of hydrothermal venting, but the validity of this relation at slow and ultraslow ridges is unproved. Here we compare hydrothermal plume surveys along three sections of the Gakkel Ridge (Arctic Ocean) and the Southwest Indian Ridge (SWIR) to determine if hydrothermal activity is similarly distributed among these ultraslow ridge sections and if these distributions follow the hypothesized linear trend derived from surveys along fast ridges. Along the Gakkel Ridge, most apparent vent sites occur on volcanic highs, and the extraordinarily weak vertical density gradient of the deep Arctic permits plumes to rise above the axial bathymetry. Individual plumes can thus be extensively dispersed along axis, to distances >200 km, and ∼75% of the total axial length surveyed is overlain by plumes. Detailed mapping of these plumes points to only 9–10 active sites in 850 km, however, yielding a site frequency F s , sites/100 km of ridge length, of 1.1–1.2. Plumes detected along the SWIR are considerably less extensive for two reasons: an apparent paucity of active vent fields on volcanic highs and a normal deep-ocean density gradient that prevents extended plume rise. Along a western SWIR section (10°–23°E) we identify 3–8 sites, so F s = 0.3–0.8; along a previously surveyed 440 km section of the eastern SWIR (58°–66°E), 6 sites yield F s = 1.3. Plotting spreading rate (us) versus F s, the ultraslow ridges and eight other ridge sections, spanning the global range of spreading rate, establish a robust linear trend (F s = 0.98 + 0.015us), implying that the long-term heat supply is the first-order control on the global distribution of hydrothermal activity. Normalizing F s to the delivery rate of basaltic magma suggests that ultraslow ridges are several times more efficient than faster-spreading ridges in supporting active vent fields. This increased efficiency could derive from some combination of three-dimensional magma focusing at volcanic centers, deep mining of heat from gabbroic intrusions and direct cooling of the upper mantle, and nonmagmatic heat supplied by exothermic serpentinization.This research was partially supported the NOAA VENTS Program. P.J.M. and H.J.B.D. gratefully acknowledge NSF grant OPP 9911795 for support of the AMORE Expedition; P.J.M. and E.T.B. acknowledge NSF grant OPP 0107767 and the VENTS Program for development and construction of MAPRs for use in ice-covered seas. H.J.B.D. acknowledges NSF grant OCE-9907630 for support of SWIR studies. J.E.S. was supported by Deutsche Forschungsgemeinschaft grant SN15/2

Assessment of infectious diseases risks from dental aerosols in real-world settings

BACKGROUND: Infectious diseases physicians are leaders in assessing the health risks in a variety of community settings. An understudied area with substantial controversy is the safety of dental aerosols. Previous studies have used in vitro experimental designs and/or indirect measures to evaluate bacteria and viruses from dental surfaces. However, these findings may overestimate the occupational risks of dental aerosols. The purpose of this study was to directly measure dental aerosol composition to assess the health risks for dental healthcare personnel and patients. METHODS: We used a variety of aerosol instruments to capture and measure the bacterial, viral, and inorganic composition of aerosols during a variety of common dental procedures and in a variety of dental office layouts. Equipment was placed in close proximity to dentists during each procedure to best approximate the health risk hazards from the perspective of dental healthcare personnel. Devices used to capture aerosols were set at physiologic respiration rates. Oral suction devices were per the discretion of the dentist. RESULTS: We detected very few bacteria and no viruses in dental aerosols-regardless of office layout. The bacteria identified were most consistent with either environmental or oral microbiota, suggesting a low risk of transmission of viable pathogens from patients to dental healthcare personnel. When analyzing restorative procedures involving amalgam removal, we detected inorganic elements consistent with amalgam fillings. CONCLUSIONS: Aerosols generating from dental procedures pose a low health risk for bacterial and likely viral pathogens when common aerosol mitigation interventions, such as suction devices, are employed

Tropomyosin Regulates Cell Migration during Skin Wound Healing

Precise orchestration of actin polymer into filaments with distinct characteristics of stability, bundling, and branching underpins cell migration. A key regulator of actin filament specialization is the tropomyosin family of actin-associating proteins. This multi-isoform family of proteins assemble into polymers that lie in the major groove of polymerized actin filaments, which in turn determine the association of molecules that control actin filament organization. This suggests that tropomyosins may be important regulators of actin function during physiological processes dependent on cell migration, such as wound healing. We have therefore analyzed the requirement for tropomyosin isoform expression in a mouse model of cutaneous wound healing. We find that mice in which the 9D exon from the TPM3/γTm tropomyosin gene is deleted (γ9D -/-) exhibit a more rapid wound-healing response 7 days after wounding compared with wild-type mice. Accelerated wound healing was not associated with increased cell proliferation, matrix remodeling, or epidermal abnormalities, but with increased cell migration. Rac GTPase activity and paxillin phosphorylation are elevated in cells from γ9D -/- mice, suggesting the activation of paxillin/Rac signaling. Collectively, our data reveal that tropomyosin isoform expression has an important role in temporal regulation of cell migration during wound healing.(NHMRC) grant 51225

Challenging claims in the study of migratory birds and climate change

Recent shifts in phenology in response to climate change are well established but often poorly understood. Many animals integrate climate change across a spatially and temporally dispersed annual life cycle, and effects are modulated by ecological interactions, evolutionary change and endogenous control mechanisms. Here we assess and discuss key statements emerging from the rapidly developing study of changing spring phenology in migratory birds. These well-studied organisms have been instrumental for understanding climate-change effects, but research is developing rapidly and there is a need to attack the big issues rather than risking affirmative science. Although we agree poorly on the support for most claims, agreement regarding the knowledge basis enables consensus regarding broad patterns and likely causes. Empirical data needed for disentangling mechanisms are still scarce, and consequences at a population level and on community composition remain unclear. With increasing knowledge, the overall support (‘consensus view’) for a claim increased and between-researcher variability in support (‘expert opinions') decreased, indicating the importance of assessing and communicating the knowledge basis. A proper integration across biological disciplines seems essential for the field's transition from affirming patterns to understanding mechanisms and making robust predictions regarding future consequences of shifting phenologies

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain

[EN] Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol's progressively enhanced addictive potencyThis work was supported by the European Union's Horizon 2020 research and innovation program (668863-SyBil-AA) and the ERA-NET NEURON program (FKZ 01EW1112-TRANSALC and PIM2010ERN-00679), as well as the Spanish State Research Agency through the Severo Ochoa Program for Centres of Excellence in R&D (SEV-2017-0723), the Deutsche Forschungsgemeinschaft (center grant TRR265-B08), and the Czech Science Foundation (GACR; grant no. 16-10214S to L.V.). S.C. and D.M. further acknowledge financial support from the Ministerio de Economia y Competitividad (MINECO) and FEDER funds under grant nos. BFU2015-64380-C2-1-R, BFU2015-64380-C2-2-R, and PGC2018-101055-B-I00 and the Generalitat Valenciana through the Prometeo Program (PROMETEO/2019/015). S.C. also acknowledges support of the Ministerio de Sanidad, Servicios Sociales e Igualdad (#2017I065). E.S. acknowledges financial support from the Slovak Research and Development Agency (APVV-17-0642). S.D.S. is supported by a NARSAD Young Investigator Grant (grant no. 25104), by the European Research Council through a Marie Sklodowska-Curie Individual Fellowship (grant no. 749506), and by the Generalitat Valenciana grant SEJI/2019/038. R.C. is supported by the NIAAA grant AA017447. W.H.S acknowledges support from the Bundesministerium fur Bildung und Forschung (BMBF; FKZ: 031L0190A, 01ZX1909CA).De Santis, S.; Cosa-Liñán, A.; Garcia-Hernandez, R.; Dmytrenko, L.; Vargova, L.; Vorisek, I.; Stopponi, S.... (2020). Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain. Science Advances. 6(26):1-12. https://doi.org/10.1126/sciadv.aba0154S11262

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence

[EN] IntroductionAlcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology.Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.The authors acknowledge funding from the European Union Horizon 2020 research and innovation program under Grant Agreement No. 668863 (SyBil-AA), and the Spanish Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (PID2021-128158NB-C21 [to S.C.] and PID2021-128909NA-I00 [to S.D.S.]) and Programs for Centres of Excellence in R&D Severo Ochoa (CEX2021-001165-S [to S.C. and S.D.S.]), the Spanish Generalitat Valenciana Government (PROMETEO/2019/015 [to SC] and CIDEGENT/2021/015 [to SDS]), the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad (#2021I082). W.H.S., F.K. and P.K. further acknowledge funding by the Deutsche Forschungs Gesellschaft through the Collaborative research Center grant TRR265 EnCoDe [138]. F.K. and P.K. also acknowledge funding by the Deutsche Forschungs Gesellschaft through the Collaborative Research Center SFB636 (Project D6). Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.Pérez-Cervera, L.; De Santis, S.; Marcos, E.; Ghorbanzad-Ghaziany, Z.; Trouvé-Carpena, A.; Selim, MK.; Pérez-Ramírez, Ú.... (2023). Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence. Acta Neuropathologica Communications. 11(1):1-21. https://doi.org/10.1186/s40478-023-01597-812111

‘‘Epic ear defence’’—a game to educate children on the risks of noise-related hearing loss

Hearing loss resulting from overexposure to entertainment-related sounds is a modern concern. ‘‘Epic Ear Defence’’ places the player in the three-dimensional environment of the ear canal and challenges the player to defend the ear from various noises, to delay the onset of noise-related hearing loss.Chevron Australia provided funding through their Community Donations Schemehttp://www.liebertpub.com/g4ham201