Minimum target prices for production of direct acting antivirals and associated diagnostics to combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182

The social impact of emotional tears

The question what specific functions the production of emotional tears fulfills has received only limited attention of behavioral scientists. We report the results of two studies on the social impact of emotional tears. In Study 1 (96 Dutch females), perceived helplessness and felt connectedness predicted the willingness to help a person depicted as crying tearfully, while perceived friendliness did not. In Study 2 (US sample, 128 males, 68 females) all three of these variables mediated the effect the display of tears had on the willingness to help. Our results replicate and extend previous work and add to current knowledge by showing that tearful crying facilitates helping behavior and by identifying reasons why people are more willing to help criers. These findings help to put forth novel predictions on the impact of tearful crying on others. Keywords: Tears, Crying, Empathy, Prosocial behavior, Personality, Friendliness, Social connectednes

Are Ecosystem Engineering Traits Fixed or Flexible : A Study on Clonal Expansion Strategies in Co-occurring Dune Grasses

Many vegetated coastal ecosystems are formed through ecosystem engineering by clonal vegetation. Recent work highlights that the spatial shoot organization of the vegetation determines local sediment accretion and subsequently emerging landscape morphology. While this key engineering trait has been found to differ between species and prevailing environmental conditions, it remains unknown how the interplay of both factors drive shoot organization and therefore landscape morphology. Here, we compared the spatial shoot organization of young, clonally expanding plants of the two dominant European dune grass species: sand couch (Elytrigia juncea) and marram grass (Ammophila arenaria) across a range of coastal dune environments (from Denmark to France). Our results reveal that, on average, sand couch deployed a more dispersed shoot organization than marram grass, which has a patchy (Lévy-like) organization. Whereas sand couch exhibited the same expansion strategy independent of environmental conditions, marram grass demonstrated a large intraspecific variation which correlated to soil organic matter, temperature and grain size. Shoot patterns ranged from a clumped organization correlating to relatively high soil organic matter contents, temperature and small grain sizes, to a patchy configuration with intermediate conditions, and a dispersed organization with low soil organic matter, temperature and large grain size. We conclude that marram grass is flexible in adjusting its engineering capacity in response to environmental conditions, while sand couch instead follows a fixed expansion strategy, illustrating that shoot organization results from the interaction of both species-specific and environmental-specific trait expression

Establishing cordgrass plants cluster their shoots to avoid ecosystem engineering

Vegetated coastal ecosystems such as salt marshes, dunes and seagrass meadows occur at the land–sea interface—a dynamic environment typified by harsh growing conditions. These ecosystems are known as biogeomorphic landscapes because their functioning depends on biophysical interactions by which organisms engineer landforms to their own benefit. The strength of such biogeomorphic feedbacks depends on plant traits, such as stem flexibility and shoot density. Recent work demonstrated that dune grasses with similar morphological traits can build contrasting landscapes due to differences in their spatial shoot organization. However, in contrast to dune grasses that trap and stabilize sand particles in aeolian landscapes, flow attenuation in aquatic environments can generate scouring around plant stems and cause uprooting, leading to establishment thresholds for young plants. Yet, it remains unknown how findings from aeolian landscapes translate to aquatic systems and how young clonally expanding plants in hydrodynamically exposed conditions overcome these establishment thresholds by optimizing shoot placement. Here, we measured shoot patterns of 90 establishing cordgrass patches Spartina anglica at 18 European field sites that cover a broad range of hydrodynamic conditions. Next, we carried out a field experiment to investigate how observed spatial shoot patterns affect plant–sediment feedbacks. Surprisingly, field survey analyses reveal highly consistent clustered shoot patterns, regardless of environmental conditions. Experimental results demonstrate that this clustered pattern minimizes scouring compared to densely clumped organizations typically observed in established patches. Synthesis. In contrast to earlier findings highlighting that establishing dune grasses optimize their landscape engineering capacity via a flexible shoot placement strategy, we find that cordgrass instead follows a fixed strategy that minimizes engineering effects in its early life stages. We suggest that marsh grasses avoid physical stress and associated establishment thresholds in their early life stage, and switch to an ecosystem engineering strategy once established. These findings shed new light on how plant traits interact with their environment to shape the landscape and pave the way for improved restoration designs by mimicking the natural shoot organization of establishing vegetation. Read the free Plain Language Summary for this article on the Journal blog.</p

Body mass index is associated with microvascular endothelial dysfunction in patients with treated metabolic risk factors and suspected coronary artery disease

Background--Obesity is key feature of the metabolic syndrome and is associated with high cardiovascular morbidity and mortality. Obesity is associated with macrovascular endothelial dysfunction, a determinant of outcome in patients with coronary artery disease. Here, we compared the influence of obesity on microvascular endothelial function to that of established cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and smoking in patients with suspected coronary artery disease. Methods and Results--Endothelial function was assessed during postocclusive reactive hyperemia of the brachial artery and downstream microvascular beds in 108 patients who were scheduled for coronary angiography. In all patients, microvascular vasodilation was assessed using peripheral arterial tonometry; laser Doppler flowmetry and digital thermal monitoring were performed. Body mass index was significantly associated with decreased endothelium-dependent vasodilatation measured with peripheral arterial tonometry (r=0.23, P=0.02), laser Doppler flowmetry (r=0.30, P < 0.01), and digital thermal monitoring (r=0.30, P < 0.01). In contrast, hypertension, hypercholesterolemia, and smoking had no influence on microvascular vasodilatation. Especially in diabetic patients, endothelial function was not significantly reduced (control versus diabetes mellitus, mean±SEM or median [interquartile range], peripheral arterial tonometry: 1.90±0.20 versus 1.67±0.20, P=0.19, laser Doppler flowmetry: 728% [interquartile range, 427-1110] v

Raman Spectroscopy Study of alpha-, beta-, gamma-NaxCoO2 and gamma-(Ca,Sr)xCoO2

Raman spectroscopy measurements have been performed on alpha-, beta-, gamma-NaxCoO2 phases differing in their stacking of CoO6 octahedra along the c-axis direction. The results demonstrate that, in general, there are five active phonons for gamma-Na0.75CoO2, two Raman active phonons for alpha-NaCoO2, and four Raman active phonons for beta-NaCoO2. We have also performed Raman scattering measurements on several gamma-(Ca,Sr)xCoO2 (0.15 <= x <= 0.35) samples which show well-defined intercalated Ca/Sr-ordering. The experimental data show that the intercalated cation ordering could result in visible alterations on Raman spectral structures. The observations of the spectral changes along with the variation of the CoO6 stacking, as well as the intercalated Sr/Ca ordering suggest that the interlayer interaction plays an important role for understanding the lattice dynamics in this layered system.Comment: 23 pages, 5 figures, Physical Review B, in pres

Ease of use and accuracy of a perinatal measuring device (Episiometer) to ensure correct angle and length of a mediolateral episiotomy: a mixed methods study

Introduction: To guide clinicians in performing mediolateral episiotomies (MLEs) at 60‐degrees, a new clinical innovation called the 'Episiometer' was developed. The aim of this study was to assess the usability and accuracy of the Episiometer in guiding clinicians to perform a safe episiotomy in both low‐ and high‐resource settings. Design: A prospective, multi‐site Phase‐I clinical trial was conducted between January 2017 and July 2018, involving three international study sites: Australia; Papua New Guinea; and India. The study design was mixed‐methods, incorporating an explanatory sequential design using surveys, clinician interviews and patient chart review to determine the usability and accuracy of the Episiometer. The patient chart review and results of this are discussed in an accompanying article. Methods: The Episiometer is the clinical innovation designed to attain an episiotomy cutting angle of 60‐degrees. The instrument is designed to assist clinicians to make an accurate and consistent episiotomy cutting angle within a 'safe' green zone between 45–60 degrees and length of at least 4 cm. The instrument also improves the visibility of the 60‐degree line to clinicians, and provides an exact measurement for length (located on the 60‐degree angle line). Clinicians from all three sites were recruited to provide feedback and measurements of incisions performed using the Episiometer (n = 135) following attendance at a minimum of at least one training session with site coordinators. Twenty of these clinicians were then recruited randomly from the sample who responded in the surveys and interviewed face‐to‐face. Patients were followed up 6‐weeks postpartum to monitor potential complications (n = 120). Results: Overall, the Episiometer was well received by clinicians – particularly by more junior staff members who were significantly more likely to report the Episiometer as being beneficial in guiding a safe MLE compared to their more senior counterparts (P = 0.003 and P = 0.011, respectively). In addition, 89% of incisions (107/120) were within the 'safe zone' between 45‐60 degrees, and 40% (48/120) were made at exactly 60‐degrees. No patient had any degree of perineal tear at follow up. Conclusion: The Episiometer is a well‐received clinical innovation in both high‐resource and lower resource settings. When used as directed, the Episiometer produces an accurate and safe incision, and reduces variation in clinicians' performance of episiotomy

Differential Expression of Proinflammatory Cytokines and Their Inhibitors during the Course of Meningococcal Infections

Circulating concentrations of tumor necrosis factor-α (TNF), interleukin (IL)-1β, IL-6, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptors p55 (sTNFr-55) and p75 (sTNFr-75) and ex vivo production ofTNF, IL-1, IL-6, and IL-1ra using a whole blood culture system were measured during the acute and convalescent stages of meningococcal infection. Circulating TNF and IL-1 were below detection level, whereas IL-6 and IL-1ra, sTNFr-55, and sTNFr-75 were increased at admission. The ex vivo production of proinflammatory cytokines TNF, IL-1, and IL-6 was suppressed at admission and restored gradually during recovery. On the contrary, the production of the antiinflammatory IL-1ra was increased at admission. The elevated concentrations of both IL-1ra and sTNFr early in the course of infection suggest a regulatory role for these antiinflammatory compounds. The observed down-regulation of the ex vivo production of TNF, IL-1, and IL-6 and up-regulation of the production of IL-1 ra in the acute stage may indicate a protective regulation mechanis