bluuebunny/crossref_metadata_2025_split huggingface dataset:
Managing access to advanced therapy medicinal products: Challenges for NHS Wales
Authors: Champion Andrew R. , Lewis Sian , Davies Stuart , Hughes Dyfrig A. 
Published: June 2020

Advanced Therapy Medicinal Products (ATMPs), which include gene, somatic cell therapies and tissue‐engineered medicines, have the potential to transform current care pathways by offering durable and potentially curative outcomes. However, they are exceptionally expensive, with prices exceeding £1m per patient in some cases. With an expectation that a large number of ATMPs will soon gain marketing authorisation (global market is estimated to reach £9bn to £14bn by 2025), healthcare payers and providers face a number of challenges to facilitate patient access to this new category of medicines.This viewpoint reflects on the experience of introducing ATMPs into the National Health Service in Wales where £1 in every £200 spent on medicines (2019/2020) is expected to be on ATMPs for just 20 patients. Evidence to date makes it apparent that decisions regarding clinical and cost‐effectiveness and the scale of the budget impact of implementing ATMPs create both financial and health service risks. Consequently, there are significant policy implications. A critical examination is made of the approaches taken for the health technology assessment and appraisal of ATMPs, the methods of payment and service impacts of these medicines, and the approach taken to horizon scanning and subsequent modelling of the financial impact over the next 10 years.
Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans
Authors: Chiang Manting D. , Frey Karen , Lee Chris , Kharasch Evan D. , Tallchief Dani , Sawyer Christopher , Blood Jane , Back Hyunmoon , Kagan Leonid , Haroutounian Simon 
Published: June 2020

AimsChanges in serotonergic sensory modulation associated with overexpression of 5‐HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5‐HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically‐administered 5‐HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration.MethodsFifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two‐compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS.ResultsThe individual model‐estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26.ConclusionsAfter intravenous administration, CSF concentrations of ondansetron were approximately 7‐fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration–time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.
Population pharmacokinetics of olanzapine in children
Authors: Maharaj Anil R. , Wu Huali , Zimmerman Kanecia O. , Autmizguine Julie , Kalra Rohit , Al‐Uzri Amira , Sherwin Catherine M.T. , Goldstein Stuart L. , Watt Kevin , Erinjeri Jinson , Payne Elizabeth H. , Cohen‐Wolkowiez Michael , Hornik Christoph P. 
Published: June 2020

AimsThe aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model‐informed paediatric dosing scheme.MethodsThe PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults.ResultsForty‐five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2–19.2) and 14.1 kg (4.2–111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one‐compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight‐normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg.ConclusionWe developed a paediatric PopPK model for enterally‐administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.
Early phase II study of mixed 19‐peptide vaccine monotherapy for refractory triple‐negative breast cancer
Authors: Toh Uhi , Sakurai Sayaka , Saku Shuko , Takao Yuko , Okabe Mina , Iwakuma Nobutaka , Shichijo Shigeki , Yamada Akira , Itoh Kyogo , Akagi Yoshito 
Published: June 2020

AbstractWe undertook an early phase II study of mixed 19‐peptide cancer vaccine monotherapy for 14 advanced metastatic triple‐negative breast cancer (mTNBC) patients refractory to systemic chemotherapy to develop a new type of cancer vaccine. The treatment protocol consisted of a weekly vaccination for 6 weeks, and there were no severe adverse events related to the vaccination throughout the trial. Increase of peptide‐specific IgG against the vaccinated human leukocyte antigen‐matched peptides, but not against the nonmatched peptides, was positively correlated with overall survival (OS) (P < .01). The median OS was 11.5 or 24.4 months in all 14 patients or the 10 patients who completed the vaccination. The patients with lower C‐reactive protein levels or 3 or fewer systemic chemotherapies were favorable candidates for this treatment. Advancement of this therapy to the next stage of study could be warranted based on the safety and immune boosting determined herein (clinical trial registration number: UMIN000014616).
Expression of classical human leukocyte antigen class I antigens, HLA‐E and HLA‐G, is adversely prognostic in pancreatic cancer patients
Authors: Hiraoka Nobuyoshi , Ino Yoshinori , Hori Shutaro , Yamazaki‐Itoh Rie , Naito Chie , Shimasaki Mari , Esaki Minoru , Nara Satoshi , Kishi Yoji , Shimada Kazuaki , Nakamura Naoya , Torigoe Toshihiko , Heike Yuji 
Published: June 2020

AbstractThe expression of classical human leukocyte antigen class I antigens (HLA‐I) on the surfaces of cancer cells allows cytotoxic T cells to recognize and eliminate these cells. Reduction or loss of HLA‐I is a mechanism of escape from antitumor immunity. The present study aimed to investigate the clinicopathological impacts of HLA‐I and non–classical HLA‐I antigens expressed on pancreatic ductal adenocarcinoma (PDAC) cells. We performed immunohistochemistry to detect expression of HLA‐I antigens in PDAC using 243 PDAC cases and examined their clinicopathological influences. We also investigated the expression of immune‐related genes to characterize PDAC tumor microenvironments. Lower expression of HLA‐I, found in 33% of PDAC cases, was significantly associated with longer overall survival. Higher expression of both HLA‐E and HLA‐G was significantly associated with shorter survival. Multivariate analyses revealed that higher expression of these three HLA‐I antigens was significantly correlated with shorter survival. Higher HLA‐I expression on PDAC cells was significantly correlated with higher expression of IFNG, which also correlated with PD1, PD‐L1 and PD‐L2 expression. In vitro assay revealed that interferon gamma (IFNγ) stimulation increased surface expression of HLA‐I in three PDAC cell lines. It also upregulated surface expression of HLA‐E, HLA‐G and immune checkpoint molecules, including PD‐L1 and PD‐L2. These results suggest that the higher expression of HLA‐I, HLA‐E and HLA‐G on PDAC cells is an unfavorable prognosticator. It is possible that IFNγ promotes a tolerant microenvironment by inducing immune checkpoint molecules in PDAC tissues with higher HLA‐I expression on PDAC cells.
Clinical and radiographic assessment of circular versus triangular cross‐section neck Implants in the posterior maxilla: A 1‐year randomized controlled trial
Authors: Li Manni Lou , Lecloux Geoffrey , Rompen Eric , Aouini Walid , Shapira Lior , Lambert France 
Published: June 2020

AbstractObjectivesImplants with a triangular neck were recently introduced to limit peri‐implant bone loss. The primary objective of this randomized controlled trial was to compare peri‐implant bone changes of circular versus triangular cross‐section neck implants 1 year after loading. The secondary objectives were to assess buccal hard tissue thickness changes, Pink Esthetic Score (PES), and patient satisfaction.Material and methodsThirty four patients requiring replacement of the single, intercalated missing tooth of healed site for at least 4 months in the posterior maxilla were randomized into 2 groups according to the type of implant. Immediately after surgery and 1 year after final restoration, a cone beam CT (CBCT) was performed to assess proximal bone remodeling and buccal bone thickness. Peri‐implant soft tissue health, PES, and patient‐reported outcome measures (PROMs) were recorded.ResultsNo implant loss occurred within the follow‐up period. The mean ± SD peri‐implant proximal bone loss 1 year after loading was 0.22 ± 0.30 mm for triangular and 0.42 ± 0.67 mm for circular implants necks (p = .25). Peri‐implant bone loss exceeding 2 mm was observed in a single implant in the circular neck group. Buccal bone thickness remained stable and did not differ different between the 2 groups. The peri‐implant soft tissue health, PES, and patient satisfaction were also comparable.ConclusionsWithin the limitations of the present study, patient clinical and radiographic outcomes did not differ between triangular and circular cross‐section neck implants in the posterior maxilla.
A multispecies assessment of wildlife impacts on local community livelihoods
Authors: Pozo Rocío A. , LeFlore Eric G. , Duthie A. Bradley , Bunnefeld Nils , Jones Isabel L. , Minderman Jeroen , Rakotonarivo O. Sarobidy , Cusack Jeremy J. 
Published: June 2020

AbstractConflicts between the interests of agriculture and wildlife conservation are a major threat to biodiversity and human well‐being globally. Addressing such conflicts requires a thorough understanding of the impacts associated with living alongside protected wildlife. Despite this, most studies reporting on human–wildlife impacts and the strategies used to mitigate them focus on a single species, thus oversimplifying often complex systems of human–wildlife interactions. We sought to characterize the spatiotemporal patterns of impacts by multiple co‐occurring species on agricultural livelihoods in the eastern Okavango Delta Panhandle in northern Botswana through the use of a database of 3264 wildlife‐incident reports recorded from 2009 to 2015 by the Department of Wildlife and National Parks. Eight species (African elephants [Loxodonta africana], hippopotamuses [Hippopotamus amphibious], lions [Panthera leo], cheetah [Acinonyx jubatus], African wild dogs [Lycaon pictus], hyenas [Crocuta crocuta], leopards [Panthera pardus], and crocodiles [Crocodylus niloticus]) appeared on incident reports, of which 56.5% were attributed to elephants. Most species were associated with only 1 type of damage (i.e., either crop damage or livestock loss). Carnivores were primarily implicated in incident reports related to livestock loss, particularly toward the end of the dry season (May–October). In contrast, herbivores were associated with crop‐loss incidents during the wet season (November–April). Our results illustrate how local communities can face distinct livelihood challenges from different species at different times of the year. Such a multispecies assessment has important implications for the design of conservation interventions aimed at addressing the costs of living with wildlife and thereby mitigation of the underlying conservation conflict. Our spatiotemporal, multispecies approach is widely applicable to other regions where sustainable and long‐term solutions to conservation conflicts are needed for local communities and biodiversity.
Anagrelide influences thrombotic risk, and prolongs progression‐free and overall survival in essential thrombocythaemia vs hydroxyurea plus aspirin
Authors: Kellner Adam , Dombi Peter , Illes Arpad , Demeter Judit , Homor Lajos , Ercsei Ibolya , Simon Zsofia , Karadi Eva , Herczeg Jozsef , Gy Korom Viktoria , Gasztonyi Zoltan , Szerafin Laszlo , Udvardy Miklos , Egyed Miklos 
Published: June 2020

AbstractObjectiveWe report an extension study of patients with essential thrombocythaemia (ET) in the Hungarian Myeloproliferative Neoplasm (HUMYPRON) Registry, which demonstrated that over 6 years anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous thrombotic events (TEs) vs hydroxyurea+aspirin.MethodsData on patients with ET were collected through completion of a questionnaire developed according to 2008 WHO diagnostic criteria and with regard to Landolfi, Tefferi and IPSET criteria for thrombotic risk. Data were entered into the registry from 14 haematological centres. TEs, secondary malignancies, disease progression and survival were compared between patients with ET treated with anagrelide (n = 116) and with hydroxyurea+aspirin (n = 121).ResultsPatients were followed for (median) 10 years. A between‐group difference in the number of patients with TEs was observed (25.9% anagrelide vs 38.0% hydroxyurea+aspirin; P = .052). Minor arterial events were more frequently reported in the hydroxyurea+aspirin group (P < .001); there were marginally more reports of major arterial events in the anagrelide group (P = .049). TE prior to diagnosis was found to significantly influence TE incidence (P > .001). Progression‐free survival (P = .004) and survival (P = .001) were significantly increased for the anagrelide group vs hydroxyurea+aspirin.ConclusionsAnagrelide reduced TEs, and increased progression‐free and overall survival vs hydroxyurea+aspirin over (median) 10 years.
Can CRISPR gene drive work in pest and beneficial haplodiploid species?
Authors: Li Jun , Aidlin Harari Ofer , Doss Anna‐Louise , Walling Linda L. , Atkinson Peter W. , Morin Shai , Tabashnik Bruce E. 
Published: June 2020

AbstractGene drives based on CRISPR/Cas9 have the potential to reduce the enormous harm inflicted by crop pests and insect vectors of human disease, as well as to bolster valued species. In contrast with extensive empirical and theoretical studies in diploid organisms, little is known about CRISPR gene drive in haplodiploids, despite their immense global impacts as pollinators, pests, natural enemies of pests, and invasive species in native habitats. Here, we analyze mathematical models demonstrating that, in principle, CRISPR homing gene drive can work in haplodiploids, as well as at sex‐linked loci in diploids. However, relative to diploids, conditions favoring the spread of alleles deleterious to haplodiploid pests by CRISPR gene drive are narrower, the spread is slower, and resistance to the drive evolves faster. By contrast, the spread of alleles that impose little fitness cost or boost fitness was not greatly hindered in haplodiploids relative to diploids. Therefore, altering traits to minimize damage caused by harmful haplodiploids, such as interfering with transmission of plant pathogens, may be more likely to succeed than control efforts based on introducing traits that reduce pest fitness. Enhancing fitness of beneficial haplodiploids with CRISPR gene drive is also promising.
The future looks like the past: Introgression of domesticated Atlantic salmon escapees in a risk assessment framework
Authors: Glover Kevin A. , Wennevik Vidar , Hindar Kjetil , Skaala Øystein , Fiske Peder , Solberg Monica F. , Diserud Ola H. , Svåsand Terje , Karlsson Sten , Andersen Lasse B. , Grefsrud Ellen S. 
Published: June 2020

AbstractEscapes of domesticated fish from aquaculture, followed by interbreeding with wild conspecifics, represent a threat to the genetic integrity and evolutionary trajectory of natural populations. Approximately fifty years of Atlantic salmon production has left an unprecedented legacy of widespread introgression of domesticated escapees in wild Norwegian populations. A major question, however, is whether current aquaculture practice will lead to additional introgression in the near future. As part of the updated Norwegian risk assessment of fish farming, we conducted a risk assessment for further introgression of domesticated escapees in wild populations in Norway. Extensive data of reported numbers of escapees, observed proportions of escapees in rivers, removal of escapees pre‐spawning, and the resilience of wild populations through demographic and genetic status informed the risk assessment. The analysis revealed that rivers in 10 of the 13 aquaculture production zones covering Norway display a moderate or high risk of further introgression of domesticated escapees. This comes in addition to widespread introgression that is already documented. We therefore conclude that so long as aquaculture production continues at its present level and form, there is a moderate‐to‐high risk of further introgression of domesticated salmon in many native populations throughout much of Norway.
Nitrous oxide emissions and forage accumulation in the Brazilian Amazon forage‐livestock systems submitted to N input strategies
Authors: do Nascimento Alexandre Ferreira , de Oliveira Carine Moreira , Pedreira Bruno Carneiro , Pereira Dalton Henrique , Rodrigues Renato Ribeiro de Aragão 
Published: June 2020

AbstractIn the Brazilian Amazon, nitrogen input strategies are required to maintain forage–livestock systems productivity. However, greenhouse gases (GHG) emissions mitigation from tropical soils is also a global demand. This research aims to assess productivity and nitrous oxide (N2O) emissions from Oxisol cultivated with Marandu palisade grass (Brachiaria brizantha [Hochst. Ex A.Rich.] Stapf) submitted to nitrogen (N) input strategies (N fertilization and biological N fixation) in the Brazilian Amazon. The treatments were the following: control (unfertilized); U40 (fertilized with 40 kg N/ha as urea); U80 (fertilized with 80 kg N/ha as urea); AS40 (fertilized with 40 kg N/ha as ammonium sulfate); AS80 (fertilized with 80 kg N/ha as ammonium sulfate); and IAB (inoculated with Azospirillum brasilense). From January to March 2016, soil N2O emission, forage accumulation (FA) and relative emission (RE) were assessed during two 28‐day cycles. The FA was greater in the U80 and AS80 than in control and IAB. The highest peaks of soil N2O flux occurred from 4 to 7 days after N fertilization, primarily in the highest N rates treatments. Overall, 40 kg N/ha resulted in higher N2O flux than control and IAB, which were lower than 80 kg N/ha regardless of the N source. The lowest fluxes occurred in the control and IAB (below 20 μg N‐N2O m−2 hr−1). All of the emission factors (EF) calculated for both fertilizers and rates were lower than 0.35%, which is below the 1% established by the IPCC. Our results indicate the need for discussion of the EF in the pasture intensification to contribute to avoid deforestation and mitigating emissions. The inputs of 40 kg N/ha per application with urea or ammonium sulfate, due to the low EF and RE, are recommended as a pasture N input strategy in the Brazilian Amazon.
The critical need for postmarketing surveillance in gene therapy for haemophilia
Authors: Konkle Barbara A. , Recht Michael , Hilger Anneliese , Marks Peter 
Published: June 2020

AbstractIntroductionThe goal of gene therapy for haemophilia is to alter the clinical phenotype to a milder form or even cure, by increasing endogenous coagulation factor levels through transfer of a functional gene encoding the respective deficient coagulation factor and subsequent transgene expression. Over the past decade, there has been tremendous progress in gene therapy, particularly in use of liver‐directed adeno‐associated viral vectors, such that several programmes for both haemophilia A and B are in phase 3 trials. With regulatory approval of the first gene therapy product expected as early as mid‐2020, there is an urgent need for a mechanism to collect long‐term data on safety and variability and durability of efficacy. There will be elements required by regulators for postmarketing surveillance and additional data needed to enhance our understanding of gene therapy outcomes and their impact on the lives of people with haemophilia.AimThe aim of this manuscript was to describe efforts underway by the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to collect long‐term harmonized data and considerations of the European and US regulatory agencies, which will inform ongoing data collection.MethodsThe status of data collection around gene therapy in haemophilia and important outcome measures were obtained by literature review. Each author described elements relevant to the activities of their organization.ConclusionSupport of all stakeholders in gene therapy, providers, patients, industry and regulators, augers successful capture of uniform long‐term safety and efficacy data to ensure optimal treatment of people with haemophilia.
The World Federation of Hemophilia Annual Global Survey 1999‐2018
Authors: Stonebraker Jeffrey S. , Bolton‐Maggs Paula H. B. , Brooker Mark , Evatt Bruce , Iorio Alfonso , Makris Michael , O'Mahony Brian , Skinner Mark W. , Coffin Donna , Pierce Glenn F. , Tootoonchian Ellia 
Published: June 2020

AbstractIntroductionThe World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non‐governmental national organizations.AimTo describe the development, methodology and achievements of the WFH AGS over the past 20 years.MethodsThe AGS is a yearly cross‐sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues.ResultsOver the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient‐level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry.ConclusionThe AGS has provided evidence to support research, programme planning and development activities of the WFH.