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

Limited Role for C. pneumoniae, CMV and HSV-1 in Cerebral Large and Small Vessel Atherosclerosis

Aims: To explore whether Chlamydia pneumoniae, Cytomegalovirus and Herpes Simplex Virus type 1 could be detected in large and small cerebral arteries, as well as in an area of brain parenchyma where white matter lesions (leukoaraiosis) can be found, in patients with clinically unmanifested cerebrovascular atherosclerosis. Methods and results( Arterial specimens from the basilar artery and middle cerebral artery, and brain samples from the basal ganglia and periventricular white matter were obtained. Neuropathological changes were assessed in Haematoxylin-Eosin stained sections. Polymerase chain reaction (PCR) was performed on paraffin embedded sections. Subsequently, we performed immunohistochemical staining on samples, which were found positive in PCR. We failed to detect C. pneumoniae, CMV, or HSV-1, in any of the cerebral large vessels. In the brain tissue, we found only one case positive for CMV, and one for C. pneumoniae. Conclusions (our findings suggest a limited role for C. pneumoniae, CMV and HSV-1 in cerebral large and small vessel atherosclerosis

Optical mammography combined with fluorescence imaging: lesion detection using scatterplots

Using scatterplots of 2 or 3 parameters, diffuse optical tomography and fluorescence imaging are combined to improve detectability of breast lesions. Small or low contrast phantom-lesions that were missed in the optical and fluorescence images were detected in the scatterplots. In patient measurements, all tumors were visible and easily differentiated from artifacts and areolas in the scatterplots. The different rate of intake and wash out of the fluorescent contrast agent in the healthy versus malignant tissues was also observed in the scatterplot: this information can be used to discriminate malignant lesion from normal structures

Tunable distribution of silica nanoparticles in water-borne coatings via strawberry supracolloidal dispersions

Hypothesis: Water-borne coatings are rapidly expanding as sustainable alternatives to organic solvent-borne systems. Inorganic colloids are often added to aqueous polymer dispersions to enhance the performance of water-borne coatings. However, these bimodal dispersions have many interfaces which can result in unstable colloids and undesirable phase separation. The covalent bonding between individual colloids, on a polymer-inorganic core-corona supracolloidal assembly, could reduce or suppress instability and phase separation during drying of coatings, advancing its mechanical and optical properties. Methods: Aqueous polymer-silica supracolloids with a core-corona strawberry configuration were used to precisely control the silica nanoparticles distribution within the coating. The interaction between polymer and silica particles was fine-tuned to obtain covalently bound or physically adsorbed supracolloids. Coatings were prepared by drying the supracolloidal dispersions at room temperature, and their morphology and mechanical properties were interconnected. Findings: Covalently bound supracolloids provided transparent coatings with a homogeneous 3D percolating silica nanonetwork. Supracolloids having physical adsorption only, resulted in coatings with a stratified silica layer at interfaces. The well-arranged silica nanonetworks strongly improve the storage moduli and water resistance of the coatings. These supracolloidal dispersions offer a new paradigm for preparing water-borne coatings with enhanced mechanical properties and other functionalities, like structural color.</p

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

Disentangling genetic and non-genetic components of yield trends of Dutch forage crops in the Netherlands

Grass and forage maize are important forage crops in ruminant production systems in the temperate regions in northwest Europe. High yields of these crops contribute to farm profitability and local provision of feed, and hence local circularity of biomass and nutrients. Variety choice is an important option to raise potential and actual yields. We analysed 40 years of perennial ryegrass and 25 years of forage maize yield data from Value of Culture and Use (VCU) experiments to determine genetic and non-genetic trends of yields in time. For maize, we calculated an annual genetic trend of +173 kg DM ha−1 and a non-genetic trend of +65 kg DM ha−1. Further analysis of the non-genetic trend showed that maize yields increased with increasing temperature sum during the growing season, and with earlier sowing. The feeding value of forage maize showed a genetic trend of +1.7 feed unit milk (VEM) kg DM−1 year−1. The annual genetic gain of perennial ryegrass was +44 kg DM ha−1. In the grass trials we found opposing non-genetic trends for cutting and grazing. Further analysis of the non-genetic trend showed that drought and the number of days with ground frost during the growing season had a negative effect on yield. We compared the average yields and trends in VCU trials with those of on-farm yields. The on-farm maize yields showed an annual trend of +195 kg DM ha−1. We estimated an average realisation of the genetic gains of 75 % in farming practice, implying a widening gap between genetic potential and on-farm yields. Averaged over the entire period, on-farm maize yields were 4.6 t DM ha−1 (24%) lower than the yields of the VCU trials. The average annual on-farm grass yields did not show any trend, and were 1.6 t DM ha−1 (13%) lower than the yields of the VCU trials. In conclusion, our study revealed significant positive genetic and varying non-genetic trends in DM yields of forage maize and perennial ryegrass, the two dominant forage crops in the Netherlands. On-farm yields showed significant positive trends for forage maize, but no trend for grassland.</p