An Economic Justification for Open Access to Essential Medicine Patents in Developing Countries

This paper offers an economic rationale for compulsory licensing of needed medicines in developing countries. The patent system is based on a trade-off between the “deadweight losses” caused by market power and the incentive to innovate created by increased profits from monopoly pricing during the period of the patent. However, markets for essential medicines under patent in developing countries with high income inequality are characterized by highly convex demand curves, producing large deadweight losses relative to potential profits when monopoly firms exercise profit-maximizing pricing strategies. As a result, these markets are systematically ill-suited to exclusive marketing rights, a problem which can be corrected through compulsory licensing. Open licenses that permit any qualified firm to supply the market on the same terms, such as may be available under licenses of right or essential facility legal standards, can be used to mitigate the negative effects of government-granted patents, thereby increasing overall social welfare

Molecular Characterisation of Bacteriophage K Towards Applications for the Biocontrol of Pathogenic Staphylococci

End of project reportThe aim of this work was to characterise staphylococcal bacteriophage (a bacterial virus) and to assess their potential as therapeutic agents against pathogenic strains of Staphylococcus aureus, particularly mastitis-causing strains. The project included the use of two newly isolated phage CS1 and DW2, and an existing polyvalent phage. The new phage were isolated from the farmyard and characterised by electron microscopy and restriction analysis. Both phage were shown to belong to the Siphoviridae family and were lytic for representatives of all three clonal groups of Irish mastitis-associated staphylococci. A cocktail of three phage (CS1, DW2 and K) at 108 (plaque forming units) PFU/ml was infused into cows teats in animal trials. The lack of an increase in somatic cell counts in milks indicated strongly that the phage did not irritate the animal. In addition, the most potent phage used in this study, phage K, was further studied by genome sequencing, which revealed a linear DNA genome of 127,395 base pairs, which encodes 118 putative ORFs (open reading frames)

SHEPHARD: A modular and extensible software architecture for analyzing and annotating large protein datasets

MOTIVATION: The emergence of high-throughput experiments and high-resolution computational predictions has led to an explosion in the quality and volume of protein sequence annotations at proteomic scales. Unfortunately, sanity checking, integrating, and analyzing complex sequence annotations remains logistically challenging and introduces a major barrier to entry for even superficial integrative bioinformatics. RESULTS: To address this technical burden, we have developed SHEPHARD, a Python framework that trivializes large-scale integrative protein bioinformatics. SHEPHARD combines an object-oriented hierarchical data structure with database-like features, enabling programmatic annotation, integration, and analysis of complex datatypes. Importantly SHEPHARD is easy to use and enables a Pythonic interrogation of largescale protein datasets with millions of unique annotations. We use SHEPHARD to examine three orthogonal proteome-wide questions relating protein sequence to molecular function, illustrating its ability to uncover novel biology. AVAILABILITY AND IMPLEMENTATION: We provided SHEPHARD as both a stand-alone software package (https://github.com/holehouse-lab/shephard), and as a Google Colab notebook with a collection of precomputed proteome-wide annotations (https://github.com/holehouse-lab/shephard-colab)

Molecular dissection of RbpA-mediated regulation of fidaxomicin sensitivity in mycobacteria

RNA polymerase (RNAP) binding protein A (RbpA) is essential for mycobacterial viability and regulates transcription initiation by increasing the stability of the RNAP-promoter open complex (R

In Vitro Analysis of Immersed Human Tissues by Raman Microspectroscopy

Raman microspectroscopy is a powerful tool for the analysis of tissue sections, providing a molecular map of the investigated samples. Nevertheless, data pre-processing and, particularly, the removal of the broad background to the spectra remain problematic. Indeed, the physical origin of the background has not been satisfactorily determined. Using 785 nm as source in a confocal geometry, it is demonstrated for the example of the protein kappa-elastin that the background and resulting quality of the recorded spectrum are dependent on the morphology of the sample. Whereas a fine powder yields a dominant broad background, compressed pellets and solution-cast thin films produce, respectively, improved quality spectra and significantly reduced spectral background. As the chemical composition of the samples is identical, the background is ascribed to stray light due to diffuse scattering rather than an intrinsic photoluminescence. The recorded spectra from a tissue sample exhibit a large and spatially variable background, resulting in poorly defined spectral features. A significant reduction of the background signal as well as improvement of the spectral quality is achieved by immersion of the sample in water and measurement with an immersion objective. The significant improvement in signal to background is attributed to a reduction of the diffuse scattering due to a change in the effective morphology as a result of an improved index matching at the water/tissue interface compared to the air/tissue interface. Compared to sections measured in air, the background is reduced to that of the water, and pre-processing is reduced to the subtraction of the substrate and water signal and correction for the instrument response, both of which are highly reproducible. Data pre-processing is thus greatly simplified and the results significantly more reliable

A modelling approach to investigate the impact of consumption of three different beef compositions on human dietary fat intakes

Objective: To apply a dietary modelling approach to investigate the impact of substituting beef intakes with three types of alternative fatty acid (FA) composition of beef on population dietary fat intakes. Design: Cross-sectional, national food consumption survey – the National Adult Nutrition Survey (NANS). The fat content of the beef-containing food codes (n 52) and recipes (n 99) were updated with FA composition data from beef from animals receiving one of three ruminant dietary interventions: grass-fed (GRASS), grass finished on grass silage and concentrates (GSC) or concentrate-fed (CONC). Mean daily fat intakes, adherence to dietary guidelines and the impact of altering beef FA composition on dietary fat sources were characterised. Setting: Ireland. Participants: Beef consumers (n 1044) aged 18–90 years. Results: Grass-based feeding practices improved dietary intakes of a number of individual FA, wherein myristic acid (C14 : 0) and palmitic acid (C16 : 0) were decreased, with an increase in conjugated linoleic acid (C18 : 2c9,t11) and trans-vaccenic acid (C18 : 1t11; P < 0·05). Improved adherence with dietary recommendations for total fat (98·5 %), SFA (57·4 %) and PUFA (98·8 %) was observed in the grass-fed beef scenario (P < 0·001). Trans-fat intakes were increased significantly in the grass-fed beef scenario (P < 0·001). Conclusions: To the best of our knowledge, the present study is the first to characterise the impact of grass-fed beef consumption at population level. The study suggests that habitual consumption of grass-fed beef may have potential as a public health strategy to improve dietary fat quality

Risk Prediction in Aortic Valve Replacement: Incremental Value of the Preoperative Echocardiogram

Background: Risk prediction is a critical step in patient selection for aortic valve replacement (AVR), yet existing risk scores incorporate very few echocardiographic parameters. We sought to evaluate the incremental predictive value of a complete echocardiogram to identify high‐risk surgical candidates before AVR. Methods and Results: A cohort of patients with severe aortic stenosis undergoing surgical AVR with or without coronary bypass was assembled at 2 tertiary centers. Preoperative echocardiograms were reviewed by independent observers to quantify chamber size/function and valve function. Patient databases were queried to extract clinical data. The cohort consisted of 432 patients with a mean age of 73.5 years and 38.7% females. Multivariable logistic regression revealed 3 echocardiographic predictors of in‐hospital mortality or major morbidity: E/e’ ratio reflective of elevated left ventricular (LV) filling pressure; myocardial performance index reflective of right ventricular (RV) dysfunction; and small LV end‐diastolic cavity size. Addition of these echocardiographic parameters to the STS risk score led to an integrated discrimination improvement of 4.1% (P<0.0001). After a median follow‐up of 2 years, Cox regression revealed 5 echocardiographic predictors of all‐cause mortality: small LV end‐diastolic cavity size; LV mass index; mitral regurgitation grade; right atrial area index; and mean aortic gradient <40 mm Hg. Conclusions: Echocardiographic measures of LV diastolic dysfunction and RV performance add incremental value to the STS risk score and should be integrated in prediction when evaluating the risk of AVR. In addition, findings of small hypertrophied LV cavities and/or low mean aortic gradients confer a higher risk of 2‐year mortality

Sustainable Financing of Innovative Therapies: A Review of Approaches

The process of innovation is inherently complex, and it occurs within an even more complex institutional environment characterized by incomplete information, market power, and externalities. There are therefore different competing approaches to supporting and financing innovation in medical technologies, which bring their own advantages and disadvantages. This article reviews value- and cost-based pricing, as well direct government funding, and cross-cutting institutional structures. It argues that performance-based risk-sharing agreements are likely to have little effect on the sustainability of financing; that there is a role for cost-based pricing models in some situations; and that the push towards longer exclusivity periods is likely contrary to the interests of industry

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29