Market access agreements for pharmaceuticals in Europe: diversity of approaches and underlying concepts

<p>Abstract</p> <p>Background</p> <p>Market Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden.</p> <p>Discussion</p> <p>We distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period.</p> <p>Summary</p> <p>We are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system.</p

What is the contribution of physician associates in hospital care in England? A mixed methods, multiple case study.

OBJECTIVES: To investigate the deployment of physician associates (PAs); the factors supporting and inhibiting their employment and their contribution and impact on patients' experience and outcomes and the organisation of services. DESIGN: Mixed methods within a case study design, using interviews, observations, work diaries and documentary analysis. SETTING: Six acute care hospitals in three regions of England in 2016-2017. PARTICIPANTS: 43 PAs, 77 other health professionals, 28 managers, 28 patients and relatives. RESULTS: A key influencing factor supporting the employment of PAs in all settings was a shortage of doctors. PAs were found to be acceptable, appropriate and safe members of the medical/surgical teams by the majority of doctors, managers and nurses. They were mainly deployed to undertake inpatient ward work in the medical/surgical team during core weekday hours. They were reported to positively contribute to: continuity within their medical/surgical team, patient experience and flow, inducting new junior doctors, supporting the medical/surgical teams' workload, which released doctors for more complex patients and their training. The lack of regulation and attendant lack of authority to prescribe was seen as a problem in many but not all specialties. The contribution of PAs to productivity and patient outcomes was not quantifiable separately from other members of the team and wider service organisation. Patients and relatives described PAs positively but most did not understand who and what a PA was, often mistaking them for doctors. CONCLUSIONS: This study offers new insights concerning the deployment and contribution of PAs in medical and surgical specialties in English hospitals. PAs provided a flexible addition to the secondary care workforce without drawing from existing professions. Their utility in the hospital setting is unlikely to be completely realised without the appropriate level of regulation and authority to prescribe medicines and order ionising radiation within their scope of practice

Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of IFN-lambda against norovirus and reovirus

Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo. Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1(−/−) mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections

Phytochemical studies, in vitro antioxidant and antiproliferative of the stem bark of Boswellia dalzielii hutch

This work aims to evaluate the total phenolic and flavonoid contents, and antioxidant and Antiproliferative activities of the stem bark of Boswellia dalzielii. Hundred gram (100 g) of methanolic extract was re-dissolved in 70% methanol and partitioned exhaustively with different solvent hexane and ethyl acetate in a separating funnel; and this method gave three fractions, hexane fraction, ethyl acetate fraction and aqueous extract. The ethyl acetate fraction was subjected to Accelerated Gradient Chromatographic due to its higher activity over the hexane fraction and four sub-fractions were obtained. Standard methods were used to determine flavonoid and phenolic contents of the methanolic, aqueous, ethyl acetate and hexane fractions and their sub-fractions. Standard methods were used to determine flavonoid and phenolic contents of the methanolic, aqueous, ethyl acetate and hexane extracts and their sub-fractions. The antioxidant property of the extracts was determined using DPPH radical scavenging and FRAP assay. Growth inhibitory activity was carried out on the crude extracts and sub-fractions using Sorghum bicolor seeds. The phenolic content was found to be highest in sub-fraction C (481.20 ± 10.13 mg GAE/g) and flavonoid contents were found to be highest in methanolic extract (142.17 ± 4.82 mg RE/g). Boswellia dalzielii stem bark exhibited antioxidant capacity; and the highest antioxidant activities were recorded from aqueous extract with the IC50 1.58 and methanol extract IC50 1.99 using DPPH. FRAP assay exhibited antioxidant capacity with EC50 1.00 for aqueous extract and sub-fraction D EC50 1.25. The antiproliferative, sub-fractions C and D at 125 µg/ml gave the highest percentage of inhibition (90%) followed by sub-fraction B (50%) at 250 µg/ml. These results further showed that the stem bark of Boswellia dalzielii has antioxidant activities and antiproliferative activity on the seeds of Sorghum bicolor; and therefore possess likely an anticancer component which needs further anticancer screening

Does skeletal muscle have an 'epi'-memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise

Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can ‘remember’ early‐life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an ‘epi’‐memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re‐encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early‐life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise‐induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the ‘epi’‐memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging

Merger of white dwarf-neutron star binaries: Prelude to hydrodynamic simulations in general relativity

White dwarf-neutron star binaries generate detectable gravitational radiation. We construct Newtonian equilibrium models of corotational white dwarf-neutron star (WDNS) binaries in circular orbit and find that these models terminate at the Roche limit. At this point the binary will undergo either stable mass transfer (SMT) and evolve on a secular time scale, or unstable mass transfer (UMT), which results in the tidal disruption of the WD. The path a given binary will follow depends primarily on its mass ratio. We analyze the fate of known WDNS binaries and use population synthesis results to estimate the number of LISA-resolved galactic binaries that will undergo either SMT or UMT. We model the quasistationary SMT epoch by solving a set of simple ordinary differential equations and compute the corresponding gravitational waveforms. Finally, we discuss in general terms the possible fate of binaries that undergo UMT and construct approximate Newtonian equilibrium configurations of merged WDNS remnants. We use these configurations to assess plausible outcomes of our future, fully relativistic simulations of these systems. If sufficient WD debris lands on the NS, the remnant may collapse, whereby the gravitational waves from the inspiral, merger, and collapse phases will sweep from LISA through LIGO frequency bands. If the debris forms a disk about the NS, it may fragment and form planets.Comment: 28 pages, 25 figures, 6 table

The Probability Distribution of Binary Pulsar Coalescence Rate Estimates. II. Neutron Star-White Dwarf Binaries

We consider the statistics of pulsar binaries with white dwarf companions (NS-WD). Using the statistical analysis method developed by Kim et al. (2003) we calculate the Galactic coalescence rate of NS-WD binaries due to gravitational-wave emission. We find that the most likely values for the total Galactic coalescence rate (R_tot) of NS-WD binaries lie in the range 0.2--10 per Myr depending on different assumed pulsar population models. For our reference model, we obtain R_tot=4.11_(-2.56)^(+5.25) per Myr at a 68% statistical confidence level. These rate estimates are not corrected for pulsar beaming and as such they are found to be about a factor of 20 smaller than the Galactic coalescence rate estimates for double neutron star systems. Based on our rate estimates, we calculate the gravitational-wave background due to coalescing NS-WD binaries out to extragalactic distances within the frequency band of the Laser Interferometer Space Antenna. We find the contribution from NS-WD binaries to the gravitational-wave background to be negligible.Comment: 20 pages, 2 figures, 2 tables, Accepted for publication in Ap