Reconfiguring global pharmaceutical value networks through targeted technology interventions

Targeting a series of advanced manufacturing technology (AMT) ‘interventions’ provides the potential for significant step changes across the pharmaceutical value chain, from early stage ‘system discovery’ and clinical trials, through to novel service supply models. This research explores future value network configurations which, when aligned with disruptive shifts in technology (process and digital), may enable alternative routes to medicines production and the delivery of additional value to ‘end-users’, i.e. patients and health care providers. We draw on a categorisation of AMTs that may enable a shift from the traditional ‘batch’ and centralised manufacturing paradigm of ‘make-to-stock’, towards more re-distributed ‘continuous’ manufacturing and ‘make-to-order’ models. Despite reported benefits in the academic literature (e.g. reduced footprints, improved quality, enhanced flexibility and inventory savings), current adoption rates of continuous technologies in this sector remain low (c. 5%). This paper presents new data sources, in our study of AMT adoption in a global pharmaceutical context – assessing the barriers to implementation, and the pathways to delivering future continuous manufacturing scenarios. Our findings capture the high level of disparity in viewpoints, highlighting the uncertainties and transformational challenges ahead – in terms of opportunity areas, technological readiness and a future vision for the sector, as a whole

Light and Life: Exotic Photosynthesis in Binary Star Systems

The potential for hosting photosynthetic life on Earth-like planets within binary/multiple stellar systems was evaluated by modelling the levels of photosynthetically active radiation (PAR) such planets receive. Combinations of M and G stars in: (i) close-binary systems; (ii) wide-binary systems and (iii) three-star systems were investigated and a range of stable radiation environments found to be possible. These environmental conditions allow for the possibility of familiar, but also more exotic forms of photosynthetic life, such as infrared photosynthesisers and organisms specialised for specific spectral niches.Comment: Accepted for publication in: Astrobiolog

QCD Chiral restoration at finite TT under the Magnetic field: Studies based on the instanton vacuum model

We investigate the chiral restoration at finite temperature $(T)$ under the strong external magnetic field $\vec{B}=B_{0}\hat{z}$ of the SU(2) light-flavor QCD matter. We employ the instanton-liquid QCD vacuum configuration accompanied with the linear Schwinger method for inducing the magnetic field. The Harrington-Shepard caloron solution is used to modify the instanton parameters, i.e. the average instanton size $(\bar{\rho})$ and inter-instanton distance $(\bar{R})$, as functions of $T$. In addition, we include the meson-loop corrections (MLC) as the large-$N_{c}$ corrections because they are critical for reproducing the universal chiral restoration pattern. We present the numerical results for the constituent-quark mass as well as chiral condensate which signal the spontaneous breakdown of chiral-symmetry (SB$\chi$S), as functions of $T$ and $B$. Besides we find that the changes for the $F_\pi$ and $m_\pi$ due to the magnetic field is relatively small, in comparison to those caused by the finite $T$ effect.Comment: 4 pages, 1 table, 6figs. arXiv admin note: significant text overlap with arXiv:1103.605

Clinical Correlates and Prognostic Significance of the Ventilatory Response to Exercise in Chronic Heart Failure

AbstractObjectives. This study sought to investigate the clinical characteristics of patients with chronic heart failure and an increased ventilatory response to exercise and to examine the prognostic usefulness of this response.Background. The ventilatory response to exercise is increased in many patients with chronic heart failure and may be characterized by the regression slope relating minute ventilation to carbon dioxide output (V̇e–V̇co2slope) during exercise.Methods. One hundred seventy-three consecutive patients (155 men; mean [±SD] age 59.8 ± 11.5 years; radionuclide left ventricular ejection fraction [LVEF] 28.4 ± 14.6%) underwent cardiopulmonary exercise testing (peak oxygen consumption 18.5 ± 7.3 ml/kg per min; V̇e–V̇co2slope 34.8 ± 10.6) over a 2-year period. Using 1.96 standard deviations above the mean V̇e–V̇co2slope of 68 healthy age-matched subjects (mean slope 26.3 ± 4.1), we defined a high ventilatory response to exercise as a slope >34.Results. Eighty-three patients (48%) had an increased V̇e–V̇co2slope (mean 43.1 ± 8.9). There was a difference in age (62.2 vs. 57.3 years, p = 0.005), New York Heart Association functional class (2.9 vs. 2.1, p < 0.001), LVEF (24.7 vs. 31.9%, p = 0.0016), peak oxygen consumption (14.9 vs. 21.7 ml/kg per min, p < 0.0001) and radiographic cardiothoracic ratio (0.58 vs. 0.55, p = 0.002) between these patients and those with a normal slope. In the univariate Cox proportional hazards model, the V̇e–V̇co2slope was an important prognostic factor (p < 0.0001). In the multivariate Cox analyses using several variables (age, peak oxygen consumption, V̇e–V̇co2slope and LVEF), the V̇e–V̇co2slope gave additional prognostic information (p = 0.018) beyond peak oxygen consumption (p = 0.022). Kaplan-Meier survival curves at 18 months demonstrated a survival rate of 95% in patients with a normal V̇e–V̇co2slope compared with 69% in those with a high slope (p < 0.0001).Conclusions. A high V̇e–V̇co2slope selects patients with more severe heart failure and is an independent prognostic marker. The V̇e–V̇co2slope may be used as a supplementary index in the assessment of patients with chronic heart failure.(J Am Coll Cardiol 1997;29:1585–90

Charge Form Factor and Cluster Structure of 6^6Li Nucleus

The charge form factor of ${}^6$Li nucleus is considered on the basis of its cluster structure. The charge density of ${}^6$Li is presented as a superposition of two terms. One of them is a folded density and the second one is a sum of ${}^4$He and the deuteron densities. Using the available experimental data for ${}^4$He and deuteron charge form factors, a good agreement of the calculations within the suggested scheme is obtained with the experimental data for the charge form factor of ${}^6$Li, including those in the region of large transferred momenta.Comment: 12 pages 5 figure

On the purification of α-cellulose from resinous wood for stable isotope (H, C and O) analysis

α-Cellulose was isolated from four samples of Scots pine (Pinus sylvestris L.). Each sample was divided into two portions. One portion had the resins removed by solvent extraction prior to removal of lignins by treatment with acidic sodium chlorite solution and treatment with sodium hydroxide solution to remove hemicelluloses. The other portion was processed in the same way apart from the solvent extraction step. The isolated wood constituents were characterised by attenuated total reflectance Fourier transform infrared (ATR/FT-IR) spectroscopy. The infrared spectra of the resulting α-cellulose samples were identical indicating that treatment with acidic sodium chlorite and sodium hydroxide was sufficient to remove resins. The values of the stable isotope ratios (carbon, oxygen and hydrogen) for each pair of α-cellulose sub-samples also showed no significant differences within the reproducibility of the methods. The implication of these studies demonstrate that the customary step of resin extraction from pine is unnecessary if sodium chlorite and sodium hydroxide are used for the isolation of α-cellulose following the technique described in this paper. In addition, the study demonstrates that the oxygen isotope ratio of the water used for cellulose extraction does not influence the stable isotope values in the α-cellulose obtained. The importance of isotopic homogeneity within the cellulose sample is also highlighted

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.Peer reviewe