bluuebunny/crossref_metadata_2025 huggingface dataset:
Symbiosis extended: exchange of photosynthetic O2 and fungal-respired CO2 mutually power metabolism of lichen symbionts
Authors: ten Veldhuis Marie-Claire , Ananyev Gennady , Dismukes G. Charles
Published: December 2019

Lichens are a symbiosis between a fungus and one or more photosynthetic microorganisms that enables the symbionts to thrive in places and conditions they could not compete independently. Exchanges of water and sugars between the symbionts are the established mechanisms that support lichen symbiosis. Herein, we present a new linkage between algal photosynthesis and fungal respiration in lichenFlavoparmelia caperatathat extends the physiological nature of symbiotic co-dependent metabolisms, mutually boosting energy conversion rates in both symbionts. Measurements of electron transport by oximetry show that photosynthetic O2is consumed internally by fungal respiration. At low light intensity, very low levels of O2are released, while photosynthetic electron transport from water oxidation is normal as shown by intrinsic chlorophyll variable fluorescence yield (period-4 oscillations in flash-induced Fv/Fm). The rate of algal O2production increases following consecutive series of illumination periods, at low and with limited saturation at high light intensities, in contrast to light saturation in free-living algae. We attribute this effect to arise from the availability of more CO2produced by fungal respiration of photosynthetically generated sugars. We conclude that the lichen symbionts are metabolically coupled by energy conversion through exchange of terminal electron donors and acceptors used in both photosynthesis and fungal respiration. Algal sugars and O2are consumed by the fungal symbiont, while fungal delivered CO2is consumed by the alga.
Design and application of adaptive PID controller based on asynchronous advantage actor–critic learning method
Authors: Sun Qifeng , Du Chengze , Duan Youxiang , Ren Hui , Li Hongqiang
Published: December 2019

To address the problems of the slow convergence and inefficiency in the existing adaptive PID controllers, we propose a new adaptive PID controller using the asynchronous advantage actor–critic (A3C) algorithm. Firstly, the controller can train the multiple agents of the actor–critic structures in parallel exploiting the multi-thread asynchronous learning characteristics of the A3C structure. Secondly, in order to achieve the best control effect, each agent uses a multilayer neural network to approach the strategy function and value function to search the best parameter-tuning strategy in continuous action space. The simulation results indicate that our proposed controller can achieve the fast convergence and strong adaptability compared with conventional controllers.
Multifractal analysis of human canine teeth at nano scale: atomic force microscopy studies
Authors: Solaymani Shahram , Ţălu Ştefan , Ghoranneviss Mahmood , Elahi Seyed Mohammad , Shafiekhani Azizollah , Hantehzadeh Mohammadreza , Nezafat Negin Beryani
Published: December 2019

The aim of the present study is to explore the 3-D micromorphology of human canine teeth materials using multifractal analysis through atomic force microscopy (AFM). The 3-D surfaces of ten extracted canine teeth of a group of 40 year old men were studied (enamel, inter enamel, inter dentin, and cementum) by AFM images in tapping mode and on square areas of 1 μm × 1 μm (512 × 512 points). The AFM images and surface multifractal analysis confirm the dependency of surface micromorphology to their structure–property of these materials across the length scales of the teeth structural architecture. Surface statistical parameters and hence, multifractal approach have been considered as reliable and sensitive tools for quantifying the 3-D surface microtexture changes of human canine teeth materials. The surface of inter dentin had the most irregular topography (the width spectrum Δα = 2.8361, value bigger than all the other Δα sample values), while the most regular topography (the width spectrum Δα = 2.6804, value lower than all the other sample values) was found in cementum. It has been concluded that multifractal analyses can be used as mathematical tools to explore the 3-D micromorphology of human canine teeth materials.
Introductory Remarks by Rebecca Gerome
Authors: Gerome Rebecca
Published: December 2019

If you follow the news, you might think that international disarmament law and policy have not been successful at preventing atrocities. Tuesday marked the fifth year of the war in Yemen. That same day, a Save the Children hospital was hit by a deadly air strike. Yesterday, the commander of U.S. forces in South Korea informed Congress that North Korea's actions are inconsistent with nuclear disarmament.
Particulars in Phaedo, 95e — 107a
Authors: White F. C.
Published: December 2019

In this paper there are two claims that I wish to defend. One is that in Socrates’ much discussed “causal” theory concrete particulars are more central than Forms. The other is that these concrete particulars are held by Plato to be not simply bundles of characteristics, not mere meeting-points of Forms, but independent individuals, existing in their own right.

It will not, I believe, be questioned that from one point of view the prime concern of the Phaedo is with concrete particulars; not with Forms, characteristics, or anything else. For, the overriding aim of the dialogue is, surely, to persuade us each to care for his own soul; it is for this reason that arguments are put forward to show that souls are indestructible. But there is no doubt that these souls are particulars.
OP14 Progress In Use Of Telerehabilitation For Persons With COPD
Authors: Hailey David , Roine Risto
Published: December 2019

Introduction

Telerehabilitation shows promise in many fields though strong evidence of benefit has been limited. We reviewed progress in the use of telerehabilitation for persons with chronic obstructive pulmonary disease (COPD). A challenge in caring for persons with this condition is the ability to achieve high levels of patient participation and compliance with rehabilitation processes.

Methods

Relevant publications were identified through literature searches from November 2009 to May 2018. We selected those that described studies of telerehabilitation in the management of COPD and reported clinical or administrative outcomes. Study quality was assessed using an approach that considers both study performance and study design. Judgments were made on whether the telerehabilitation application had been successful, if reported outcomes were clinically significant, and if further data were needed to establish the application as suitable for routine use.

Results

Twenty-five publications, on 26 studies, were selected. Twelve were of high or good quality. In 11 studies the telemedicine application was successful. Nine studies had unsuccessful applications, and for six studies success was unclear. Further data before routine use would be required or desirable for all successful applications. In many studies there were difficulties associated with availability of skilled mentors, motivational support for patients and access to reliable remote monitoring and communication technology.

Conclusions

Various types of telerehabilitation are potentially helpful in the management of COPD. Availability and access to these technologies should improve. However, in management of this clinically challenging condition their use must be linked to suitable training and education of patients with COPD and timely support for them from healthcare professionals.
OP30 Impact Of Patient Reported Outcomes Data On Health Technology Assessments Of Acute Myeloid Leukemia
Authors: Shah Manasee , Ernst Rianne , Holmstrom Stefan , van Hooijdonk Inge
Published: December 2019

Introduction

Patient-reported outcomes (PRO) data are important in understanding patients’ experience of disease and treatment; however, PRO data are not universally collected or consistently included as part of a Health Technology Assessment (HTA) submission. Additionally, the HTA bodies’ response to PRO data vary, making the impact unclear. To understand the impact of PRO data on reimbursement decisions for Acute Myeloid Leukemia (AML) indications, an in-depth analysis of HTA bodies’ appraisals of AML and analogous indications was conducted.

Methods

This analysis was conducted using IQVIA's HTA Accelerator, which contains HTA appraisals from ≥100 HTA agencies in thirty-nine countries. Included in the analysis were single-technology assessments (original submissions, resubmissions, extensions of original indications, and renewals); relevant regulatory approvals and pivotal trials were also analyzed.

Results

Of the 185 AML appraisals from sixteen HTA bodies, 66 (36%) included PRO data. Within these, thirteen different PRO instruments were identified, none of which have been validated in patients with AML. For seven of twenty in-scope products, PRO evidence positively impacted ≥1 of the HTA decisions. Although the same HTA bodies (i.e., Scottish Medicines Consortium, pan-Canadian Oncology Drug Review, and the National Institute of Health and Care Excellence) generally accepted the PRO evidence, others were critical of the evidence (i.e., Haute Autorité de Santé and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen). The most common concerns raised by the HTA bodies regarding the PRO evidence included trial design and low patient response rate.

Conclusions

Of the products that included PRO evidence in their HTA submissions, 35% received positive feedback from ≥1 HTA body on their submitted PRO evidence. Attention to PRO data collection is key to demonstrate the value of AML products to HTA bodies. Without these data, a clear gap in the understanding of patients’ experience is evident.
OP54 Monitoring Evidence On Overall Survival Benefits Of Anti-Cancer Drugs
Authors: Grössmann Nicole , Robausch Martin , Rosian Katharina , Wild Claudia , Simon Judit
Published: December 2019

Introduction

The introduction of fast-track licensing strategies increases the approval of anti-cancer drugs with ambiguous benefit-risk profiles. Thus, in many instances there is lacking evidence about overall survival (OS) at the time of marketing authorisation. Our objective was to monitor and characterise therapies with ambiguous benefit-risk profiles and identify any post-approval updates on median OS after at least three years of approval by the European Medicines Agency (EMA).

Methods

We included all originator anti-cancer drugs with initially ambiguous benefit-risk profiles that received marketing authorization from the EMA between 1 Jan 2009 and 31 May 2015. Our monitoring timeframe was at least three years after EMA-approval. To identify study updates, the following three sources were included: clinicaltrials.gov, European Public Assessment Reports (EPARs), and PubMed.

Results

In total, we identified 102 eligible approval studies. Out of these, a negative difference in median OS or no information was available in forty-three (42.2%) instances. During monitoring, eleven updates with accessible information on median OS could be identified. Including monitoring results, there are still thirty-two remaining therapies (31.4%) where no or negative information (n = 27 [26.5%] and n = 5 [4.9%], respectively) regarding median OS was present at least three years after EMA approval.

Conclusions

One-third of oncology drugs with ambiguous benefit-risk profiles failed to demonstrate a survival benefit even several years following marketing authorization. Systematic and transparent post-approval monitoring mechanisms will be of high relevance to assure a clinically relevant patient benefit, since the trend towards faster access to medicines with uncertain benefit is increasing rather than declining.
OP64 Implementation Of Whole Exome Sequencing For Rare Diseases
Authors: Fennessy Paul , Griffin Marianne
Published: December 2019

Introduction

The Victorian Department of Health and Human Services provided AUD 25 million (i.e. USD 17.3 million) over four years to determine the place of whole exome sequencing (WES) for patients attending public genetics clinics. Comparative analysis of WES and ‘usual care’ determined that WES increased diagnosis rate (from 14 to 58 percent), changed clinical management in one third of patients and identified relatives and couples at high risk of recurrence in future pregnancies. Translating this into routine care requires co-design with clinical and laboratory stakeholders.

Methods

Victoria's clinical and laboratory genetics service system uses a ‘hub and spoke’ model. Representatives from these were invited to join a ‘Clinical Adoption Group’ (CAG) to oversight implementation of new government funding (AUD 2 million (i.e. USD 1.4 million) per year) to ensure statewide access to, and funding of, WES for children with rare undiagnosed genetic conditions. The CAG developed terms of reference, ‘traffic light’ evidence-based eligibility criteria, a pricing model and reporting mechanism, and recommended funding for sequencing, curation, curator training and multidisciplinary team (MDT) meetings to support implementation.

Results

Funding was distributed across hub and spoke sites reflecting clinical and laboratory demand and workforce requirements. All cases demonstrated clinical utility and were reviewed at MDT meetings. To date, 37 percent of patients have received a diagnosis changing management, with equity of access between metropolitan and regional areas demonstrated. Eligibility criteria are reviewed as new evidence is published to ensure new evidence is incorporated, although curation capacity limits turn-around-times.

Conclusions

Co-designing a statewide and evidence-based clinical model has resulted in sector (i.e. clinician and laboratory) buy-in and supported broad access to funded WES. In addition, the sector has developed a better understanding of how evidence informs policy and funding decisions, which has resulted in delivering equitable WES that provides early diagnosis leading to changed clinical management and cessation of unnecessary interventions.
OP65 Pharmacoeconomic Evaluation Of Orphan Drugs: Impact Of Extra Criteria?
Authors: Maguire Orla , McCullagh Laura , Usher Cara , Barry Michael
Published: December 2019

Introduction

There is ongoing debate as to whether conventional pharmacoeconomic evaluation (PE) methods are appropriate for orphan medicinal products (OMPs). The National Centre for Pharmacoeconomics (NCPE) in Ireland has a well-defined process for conducting pharmacoeconomic evaluations of pharmaceuticals, which is the same for OMPs and non-OMPs. The objective of this study was to identify whether supplementary criteria considered in the pharmacoeconomic evaluation of OMPs would affect final reimbursement recommendations.

Methods

A literature search was conducted to identify criteria. Orphan drug pharmacoeconomic evaluations completed by the NCPE between January 2015 and December 2017 were identified and supplementary criteria, where feasible, were applied.

Results

Fourteen pharmacoeconomic evaluations were included in the study. Three criteria that could feasibly be applied to the NCPE evaluation process were identified, all three of which essentially broadened the economic perspective of the pharmacoeconomic evaluation. Higher cost-effectiveness threshold: Despite being arbitrarily raised from EUR 45,000/QALY to EUR 100,000/QALY, only one orphan drug demonstrated cost-effectiveness at this higher threshold. Weighted QALY gain: here, a weighted gain of between one and three is applied to drugs demonstrating QALY gains between 10 and 30, respectively. No OMPs included in the study showed a QALY gain of more than 10. Thirteen demonstrated QALY gains less than 10 and one could not be evaluated. Societal perspective: six submissions incorporated societal perspective as a scenario analysis. Despite incremental cost-effectiveness ratios (ICERs) being reduced between 4 percent and 58 percent, only two OMPs demonstrated cost-effectiveness at the higher threshold (EUR 100,000/QALY).

Conclusions

Application of supplementary criteria to the pharmacoeconomic evaluation of OMPs had a minor effect on three products assessed. However, for the majority, the final cost-effectiveness outcomes remained the same. The study highlights that other criteria are being considered in the decision to reimburse.
OP68 Value-Engineered Translation: An Example for Bladder Cancer Diagnosis
Authors: Sutton Andrew , Lamont John , Evans R. , Williamson Kate , O'Rourke Declan , Duggan Brian , Sagoo Gurdeep , Reid Cherith , Ruddock Mark
Published: December 2019

Introduction

The Institute of Health Economics offers a suite of analyses that provide developers an understanding of the expected commercial viability of an early stage health technology. In combination, these analyses form the Value-Engineered Translation framework. These methods incorporate innovative methods to manage uncertainty in early economic evaluations, in particular, moving beyond current stochastic assessments of headroom to account for inter-market variability in value hurdles, as well as incorporating social value premia considerations. An illustration of these methods is demonstrated using the example of a non-invasive diagnostic test (called DCRSHP) at an early stage of development, compared to current practice of cystoscopy in the diagnosis of bladder cancer.

Methods

Competing technologies were identified to inform the headroom assessment based on price and effectiveness. Then, a model-based cost-effectiveness analysis was undertaken incorporating headroom analysis, stochastic one-way sensitivity analysis, and value of information analysis using data from secondary sources.

Results

Currently there are a number of non-invasive tests available, but none have sufficient test accuracy to be suitable for bladder cancer diagnosis alone. From the headroom analysis, DCRSHP can be priced at up to CAD 790 (i.e. USD 588) and still be cost-effective compared to the current practice of cystoscopy. Interestingly this price can be increased for patient groups that have lower levels of bladder cancer prevalence.

Conclusions

The requirements of economic evaluations depend on the stage of technology development, and analysis approaches must reflect this. The results here indicate that DCRSHP clears the value hurdle in terms of being cost-effective, and thus provides the opportunity to make a commercial return on future investment. Future analysis of DCRSHP could consider the cost drivers for development of the technology, including the regulatory pathways, costs associated with the intellectual asset management for the technology, and alternative manufacturing costs. All of which contribute to the research-to-practice continuum.
OP72 HTA Beyond 2020 In China： HB-HTA Rising Up In Tertiary Hospitals
Authors: Lin Xia , Bai Fei , Lv Lanting , Qin Xiaoxiao
Published: December 2019

Introduction

Health technology assessment (HTA) was introduced into China more than 20 years ago and has developed rapidly recently. While only recently has the concept of hospital-based health technology assessment (HB-HTA) attracted attention in China. The purpose of this study is to investigate the views of government officials, decision makers and relevant stakeholders in the management and application of medical technologies in hospitals, within the environment of Health System Reform in China. We analysed the current situation and identified obstacles and prospects of HB-HTA in Chinese tertiary hospitals.

Methods

We conducted semi-structured interviews in 8 provinces in Eastern, Central and Western China; in 2 to 4 tertiary public hospitals in each province. We interviewed doctors, nurses, and Chiefs in hospitals, and key informants in the National Center for Medical Service Administration.

Results

A total of 98 people participated in the panel discussions and interviews. We found that:

1.

China's tertiary public hospitals have embraced HB-HTA, and various hospitals have performed different forms of HB-HTA (including ambassador model, Mini-HTA model, and internal committee model). However, the assessment process, standards, and methods are yet to be standardized.

2.

The promotion of HB-HTA in China's tertiary public hospitals has remarkable external incentives and internal advantages.

3.

The lack of HB-HTA professionals, improvements in cognition level, and evidence-based decision-making models and management culture hinders the development of HB-HTA in China.

Conclusions

HB-HTA is in high demand in China, especially in tertiary hospitals. It will continue to develop rapidly over the next decade along with the development of China's HTA. HB-HTA will complement the national HTA to jointly extend the Chinese HTA system.
OP88 Digital Approaches For Randomized Controlled Trial Recruitment Or Retention: A Systematic Map
Authors: Frampton Geoff , Shepherd Jonathan , Pickett Karen , Griffiths Gareth , Wyatt Jeremy
Published: December 2019

Introduction

Recruitment and retention of participants in randomized controlled trials (RCTs) is challenging, and is why many RCTs fail or are not completed on time. Digital approaches such as social media, data mining, email or text messaging could improve recruitment and/or retention, but how well they match these purposes is unclear. We used systematic methods to map the digital approaches that have been investigated during the past 10 years.

Methods

We searched Medline, Embase, other databases and relevant web sites in July 2018 to identify comparative studies of digital approaches for recruiting and/or retaining participants in clinical or health RCTs. Two reviewers screened references against protocol-specified eligibility criteria. Studies included were coded by one reviewer (with 20 percent checked by a second reviewer) using pre-defined keywords to describe characteristics of the studies, populations and digital approaches evaluated.

Results

We identified 9,133 potentially relevant references, of which 100, reporting 101 unique studies, met the criteria for inclusion in the map. Among these, 95 percent of studies investigated recruitment but only 11 percent investigated retention. Study areas included health promotion and public health (36 percent), cancer (17 percent), circulatory system disorders (13 percent) and mental health (10 percent). Most study designs were observational (89 percent). The most frequent digital approaches for recruitment were internet sites (53 percent of recruitment studies), social media (42 percent), television or radio (31 percent) and/or email (31 percent). For retention these were email (63 percent of retention studies) or text messaging (38 percent). Time and costs of recruitment were reported in 17 percent and 30 percent of recruitment studies respectively, whilst costs were reported in 19 percent of retention studies.

Conclusions

A wide range of digital approaches has been studied, in many combinations. Evidence gaps include lack of experimental studies; studies on retention; and studies for specific populations (e.g. children or older people) and outcomes (e.g. user satisfaction). More robust experimental studies, perhaps conducted as studies-within-a-trial (SWAT), are needed to address knowledge gaps and ensure that estimates of digital tool effectiveness and efficiency are reliable.
OP89 Conference Abstract Searching In National Institute For Health And Care Excellence Health Technology Appraisals
Authors: Wong Ruth
Published: December 2019

Introduction

The National Institute for Health and Care Excellence (NICE) guidelines manual recommend that MEDLINE, Embase and Cochrane Central Register of Controlled Trials should be prioritized for searching for reviews of the effectiveness of pharmacological interventions. Additionally, searching trial registries and conference abstracts are recommended to identify ongoing or unpublished research. However, the approaches to searching conference abstracts have not been previously studied. The aim is to analyze searches of conference abstracts reported in NICE Technology Appraisal (TA) company submissions for cancer interventions from 2013 until September 2018.

Methods

The company submissions were searched and obtained via the NICE technology appraisal guidance website. The sources used to find conference abstracts were identified from the company clinical effectiveness review search methods and appendices. Conference abstract searching in both database and website sources were compared.

Results

Of all 394 TAs, 124 (31 percent) were cancer TAs. Between 2013 and 2018, 91 TAs were completed or updated, which covered 18 cancer categories and 52 different named technologies. Technologies to treat non-small-cell lung cancer was the most frequently appraised in the last five years. Nivolumab was the most frequently appraised technology. Searches for conference abstracts were reported in 70 (77 percent) out of 91 company submissions. Supplementary searching was reported in 59 (84 percent), compared with 11 (16 percent) searching either/both Embase and the Web of Science Conference Proceeding Index (WoS-CPCI). A total of 54 supplementary website sources were searched which ranged from one to 11 per TA (average four sources). The American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology were the most frequently searched sources.

Conclusions

Whilst the WoS-CPCI has better coverage of cancer conference abstracts than Embase, searching databases alone are inadequate. Supplementary conference websites should be searched for reasons such as access to the most recent abstracts and incomplete indexing of titles within databases. A wide range of cancer specific sites exists although the impact of broad (e.g. ASCO) versus condition specific sites is unclear.
OP123 A Cost-Effectiveness Registry For Prioritization In Emerging Markets
Authors: Ollendorf Daniel , D'Cruz Brittany , Emerson Joanna , Bacon Rachel , Cohen Joshua , Neumann Peter
Published: December 2019

Introduction

Decision-makers in low- and middle-income countries (LMICs) often must prioritize health spending without quantitative benchmarks for the value of their purchases. The Tufts Global Health Cost-Effectiveness Analysis (GH CEA) Registry (healtheconomicevaluation.org/GHCEARegistry/) is a freely-available, curated and standardized dataset designed to address this need.

Methods

All indexed English-language articles published between 1995 and 2017 are currently included in the GH CEA Registry. Studies are limited to those reporting cost-effectiveness in terms of cost per disability-adjusted life years (DALYs) averted, a commonly-employed metric in global health. Abstracted data include intervention type, comparator(s), country, funding source, study characteristics (e.g., perspective, time horizon), primary study findings, sensitivity analyses, and disaggregated data on costs and DALYs. Study quality is assessed using a numerical scoring system (from 1-7, higher scores indicating better quality) based on accuracy of findings and comprehensive reporting of methods and results.

Results

To date, 620 articles have been included in the GH CEA Registry. Among LMICs, studies have been conducted primarily in Sub-Saharan Africa (41 percent) or South Asia (34 percent), have focused on communicable diseases (67 percent), and have involved immunization, educational, or pharmaceutical interventions (67 percent). As a priority-setting example, seven percent of interventions from higher-quality studies (ratings of 5 or higher) were reported to be cost-saving (i.e., lower costs and greater DALYs than standard care), two-thirds of which involved primary disease prevention (e.g., immunization, educational or behavioral interventions).

Conclusions

The GH CEA Registry is a new tool for decision-makers in LMICs, particularly those without a formal health technology assessment infrastructure but with a remit for providing access to essential, cost-effective health interventions. New functions are under development, including league tables for priority ranking, a repository for shared models, and tools for enhancing transferability between settings.
PP12 Cost-Utility Analysis Of Dolutegravir For HIV-1 Infection In Thailand
Authors: Yoopetch Panida , Khemvaranan Chalida
Published: December 2019

Introduction

HIV drug resistance (HIVDR) has significantly increased in Thailand. However, a new generation integrase inhibitor, dolutegravir, has not yet been included in the country's National List of Essential Medicines (NLEM). Since these drugs are high in costs, an economic evaluation is needed to support the decision. This study aims to assess the cost-utility analysis of dolutegravir for HIV-1 infection in Thailand.

Methods

A Markov model was developed to evaluate the cost-utility as follows: (i) the current practice of darunavir/ritonavir (DRV/r) + tenofovir (TDF) + lamivudine (3TC); (ii) DRV/r + etravirine (ETR) + TDF + 3TC; (iii) DRV/r + raltegravir (RAL) + TDF + 3TC; (iv) DRV/r + RAL + ETR; and (v) DRV/r + RAL + maraviroc (MVC); (vi) DRV/r + dolutegravir (DTG) + MVC; (vii) DRV/r + DTG + ETR; (viii) DRV/r + DTG + TDF + 3TC. The model incorporated cost data adjusted for 2017 using the consumer price index, and effectiveness data from a review of published studies. Outcomes were measured in life years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), and future costs and outcomes were discounted at 3 percent per annum. Finally, a probabilistic sensitivity analysis was conducted to deal with uncertainties around the parameters.

Results

All alternative treatment regimens for HIV patients resistant to first- and second-line antiretroviral therapies (ARTs) in Thailand were found to be not cost-effective at the willingness-to-pay (WTP) of THB 160,000/QALY (USD 5,197/QALY). However, the eighth regimen of DRV/r + DTG + TDF + 3TC had the lowest lifetime cost at THB 5.3 million (USD 172,145) while increasing QALY by approximately 14 QALYs.

Conclusions

At a societal WTP of THB 160,000 per QALY gained (USD 5,197 per QALY gained), dolutegravir for HIV patients resistant to first- and second-line ARTs in Thailand was found to be not cost-effective.
PP50 How Do Target Population Sizes In Health Technology Assessments Impact Drug Price Changes?
Authors: Liden Daniel , Jao Rachel , Lockwood Cameron , Reinaud Floriane
Published: December 2019

Introduction

The relationship between heath technology assessment (HTA) recommendations and drug prices has received little attention in the published literature. We consider whether target population sizes estimated as part of positive HTA decisions impact future price changes. We hypothesize that larger target populations may result in larger drug price reductions, as overall budget impact is an important component of price negotiations.

Methods

HTA and pricing data were obtained from the Context Matters Market Access Platform (MAP) and IHS Markit's PharmOnline International (POLI) pricing database, respectively. We analyzed 55 HTA decisions from the Gemeinsame Bundesausschuss (G-BA; Germany) and the Haute Autorité de Santé (HAS; France) for oncology products receiving European Medicines Agency approval between 2011 and the end of 2014. Pricing and HTA histories were tracked from the beginning of 2012 until October 2018. Using multiple regression to control for HTA agency, country-specific scores (Improvement in Actual Benefit and Additional Benefit scores), pack size, and initial price, we examined the relationship between a drug's price change in the year following an HTA review and the increase in target population resulting from the HTA decision.

Results

We found that larger increases in target population were related to larger reductions in drug prices (p = 0.014). The magnitude of the effect size was low.

Conclusions

For the sample evaluated, we found a small but statistically significant association between target population size increases (as estimated by HTA bodies) and price reductions, supporting our hypothesis that target population plays a role in price negotiations. Confidential discounts and managed-access agreements likely account, in part, for the low magnitude of the observed association. Future work on this topic will involve larger samples covering a greater number of HTA agencies to improve the power and generalizability of the analysis.
PP81 Real World Data: The Early Access To Medicines Scheme Catches The Worm
Authors: Hall Adam , Liu Lok Wan , Macaulay Richard , Walsh Sean
Published: December 2019

Introduction

The Early Access to Medicines Scheme (EAMS) aims to provide access to medicines prior to market authorization for patients with severe, life-threatening diseases who do not have adequate treatment options. An EAMS designation enables the potential collection of United Kingdom-specific real world evidence (RWE) prior to health technology assessment (HTA) by the National Institute for Health and Care Excellence (NICE). This research evaluates whether RWE is being gathered through the EAMS and utilized to support HTA submissions.

Methods

All EAMS designations as of 7 November 2018 were identified from the Medicines and Healthcare products Regulatory Agency website. For products with final NICE guidance, all publicly-available NICE documentation was reviewed.

Results

Sixteen product and indication pairings with an EAMS designation were identified, with 12 having received final NICE guidance (11 were recommended, 3 were recommended for temporary reimbursement via the Cancer Drugs Fund, and 2 were not recommended). Of the 11 recommended products, seven had references to the number of patients or sites with product access through the EAMS, but only one (dupilumab for atopic dermatitis) had detailed data collected during the EAMS period. The manufacturer of dupilumab reported baseline demographics and disease characteristics from a cohort of 35 patients treated under the EAMS to inform the generalizability of trial populations for clinical practice. Follow-up results from this cohort demonstrated that real-world data on dupilumab effectiveness was comparable with the clinical trial data, despite a higher proportion of patients in the real-world cohort receiving immunosuppressant therapy, which makes improvements in efficacy harder to achieve. The committee also noted that the RWE presented supported the understanding of dupilumab's long-term clinical effectiveness and informed assumptions for the economic model.

Conclusions

To date, the majority of products receiving an EAMS designation have not presented RWE at NICE reappraisal. The case of dupilumab illustrated how RWE collected through the EAMS can be used to reduce uncertainty around how clinical trial data can be translated into clinical practice. In the future, RWE may increasingly be used to help inform NICE decisions.
PP164 Improving Medical Diagnosis Through Advanced Data Analytics Tools
Authors: González-Barcina Imanol , de Vicuña-Meléndez Aitor García , Santorcuato Ana , Revuelta-Antizar Ivan , Rodríguez-Tejedor Santiago , López-Moreno Borja , Arana-Arri Eunate
Published: December 2019

Introduction

Current clinical practice is based on guidelines and local protocols that are informed by clinical evidence. This means that clinical variability is reduced, but can lead to inefficient clinical decision-making, and can increase medical errors, decreasing patient's safety. The aim of the EXCON project is to investigate the innovative concept of Intelligent Clinical History (ICH), and to develop functional prototypes of high added-value in healthcare services.

Methods

The innovative EXCON project will take advantage of recent advances in technologies for coding, structuring and semantizing medical information. Thanks to this new structuring, the EXCON platform will be developed. Final users will be health professionals and other decision-makers. Doctors, nurses, epidemiologists and information specialists will be involved in the development and subsequent validation of the platforms.

Results

To develop the ICH platform clinical data on a highly prevalent symptom with high variability in clinical practice, such as non-traumatic chest pain in emergency services, has been collected from different electronic medical record databases. The extraction of clinical data to implement new techniques of artificial intelligence requires tasks that must be automated, which today is difficult and tedious (data is often not computerized). Through techniques applied in EXCON, such as natural language processing, relevant clinical data have been extracted and a Decision Support System has been developed and validated. This tool optimizes resources and improves clinical management, reducing errors and increasing patient's safety.

Conclusions

In coming decades, patient management will be impacted by the application of new advanced data analytics tools. This will allow for safer and more efficient clinical management, decrease variability in clinical practice, and improve equity. That is why the development and assessment of these technologies is necessary.
Relevance of Relative Sea Surface Temperature for Tropical Rainfall Interannual Variability
Authors: Izumo Takeshi , Vialard Jérôme , Lengaigne Matthieu , Suresh Iyyappan
Published: December 2019

The coupling between sea surface temperature (SST) anomalies and rainfall is an important driver of tropical climate variability. Observations however reveal inconsistencies, such as decreased convective rainfall in regions with positive SST anomalies in the tropical Indian and Atlantic Oceans during and after El Niño–Southern Oscillation (ENSO) events. The upper troposphere warms during El Niño events, stabilizing the atmosphere. SST anomalies only account for the influence of the surface. Using theoretical arguments, we show that relative SST (RSST; defined as SST minus its tropical mean) anomalies, by also accounting for the influence of upper tropospheric temperature anomalies on gross moist stability, explain tropical convection interannual variations better than SST anomalies in observations and climate models. This relation further improves when RSST anomalies are weighted by the precipitation climatology to account for low and high‐precipitation regimes. Using RSST is thus essential to understand El Niño–Southern Oscillation teleconnections and interactions between modes of tropical climate variability.
Allo-HSCT recipients with invasive fungal disease and ongoing immunosuppression have a high risk for developing tuberculosis
Authors: Yang Apeng , Shi Jimin , Luo Yi , Ye Yishan , Tan Yamin , Huang He , Zhao Yanmin
Published: December 2019

Patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk of acquiring tuberculosis (TB) due to a status of immunosuppression. We conducted a nested case control study to investigate the incidence and risk factors for TB after allo-HSCT. Between 2012 and 2017, 730 consecutive allo-HSCT recipients were enrolled, and 14 patients (1.92%) were diagnosed with TB. Relatively, 54 allo-HSCT recipients were selected as control. Patients who suffered TB had a significantly higher 3-year non-relapse mortality rate than the control group (30.36% vs 5.39%, P < 0.01). In multivariate analysis, invasive fungal disease (HR 4.87, 95% CI 1.39–17.09), treatment with a relatively high dose of prednisone (HR 10.34, 95% CI 1.12–95.47) and treatment with tacrolimus (HR 4.79, 95% CI 1.18–19.44) were identified independent risk factors for TB occurrence post allo-HSCT (P < 0.05). Meanwhile, donor type, dose and type of anti-thymocyte globulin (ATG) administrated, as well as treatment intensity, did not alter the incidence of TB. Therefore, allo-HSCT recipients with unexplained fever, especially those who suffer from invasive fungal disease and ongoing immunosuppression with a relatively high dose of prednisone or tacrolimus, are at a high-risk of developing active TB. Closely Monitoring TB occurrence, making a timely diagnosis and administering the proper treatment may be beneficial to those high-risk patients.
Origin of the São Paulo Yellow Fever epidemic of 2017–2018 revealed through molecular epidemiological analysis of fatal cases
Authors: Cunha Marielton dos Passos , Duarte-Neto Amaro Nunes , Pour Shahab Zaki , Ortiz-Baez Ayda Susana , Černý Jiří , Pereira Bárbara Brito de Souza , Braconi Carla Torres , Ho Yeh-Li , Perondi Beatriz , Sztajnbok Jaques , Alves Venancio Avancini Ferreira , Dolhnikoff Marisa , Holmes Edward C. , Saldiva Paulo Hilário Nascimento , Zanotto Paolo Marinho de Andrade
Published: December 2019

The largest outbreak of yellow fever of the 21st century in the Americas began in 2016, with intense circulation in the southeastern states of Brazil, particularly in sylvatic environments near densely populated areas including the metropolitan region of São Paulo city (MRSP) during 2017–2018. Herein, we describe the origin and molecular epidemiology of yellow fever virus (YFV) during this outbreak inferred from 36 full genome sequences taken from individuals who died following infection with zoonotic YFV. Our analysis revealed that these deaths were due to three genetic variants of sylvatic YFV that belong the South American I genotype and that were related to viruses previously isolated in 2017 from other locations in Brazil (Minas Gerais, Espírito Santo, Bahia and Rio de Janeiro states). Each variant represented an independent virus introduction into the MRSP. Phylogeographic and geopositioning analyses suggested that the virus moved around the peri-urban area without detectable human-to-human transmission, and towards the Atlantic rain forest causing human spill-over in nearby cities, yet in the absence of sustained viral transmission in the urban environment.
Bleomycin hydrolase regulates the release of chemokines important for inflammation and wound healing by keratinocytes
Authors: Riise Rebecca , Odqvist Lina , Mattsson Johan , Monkley Susan , Abdillahi Suado M. , Tyrchan Christian , Muthas Daniel , Yrlid Linda Fahlén
Published: December 2019

Bleomycin hydrolase (BLMH) is a well-conserved cysteine protease widely expressed in several mammalian tissues. In skin, which contains high levels of BLMH, this protease is involved in the degradation of citrullinated filaggrin monomers into free amino acids important for skin hydration. Interestingly, the expression and activity of BLMH is reduced in patients with atopic dermatitis (AD) and psoriasis, and BLMH knockout mice acquire tail dermatitis. Apart from its already known function, we have discovered a novel role of BLMH in the regulation of inflammatory chemokines and wound healing. We show that lowered BLMH levels in keratinocytes result in increased release of the pro-inflammatory chemokines CXCL8 and GROα, which are upregulated in skin from AD patients compared to healthy individuals. Conditioned media from keratinocytes expressing low levels of BLMH increased chemotaxis by neutrophils and caused a delayed wound healing in the presence of low-level TNFα. This defective wound healing was improved by blocking the shared receptor of CXCL8 and GROα, namely CXCR2, using a specific receptor antagonist. Collectively, our results present a novel function of BLMH in regulating the secretion of chemokines involved in inflammation and wound healing in human keratinocytes.
Passenger sequences can promote interlaced dimers in a common variant of the maltose-binding protein
Authors: Momin Afaque A. , Hameed Umar F. Shahul , Arold Stefan T.
Published: December 2019

The maltose-binding protein (MBP) is one of the most frequently used protein tags due to its capacity to stabilize, solubilize and even crystallize recombinant proteins that are fused to it. Given that MBP is thought to be a highly stable monomeric protein with known characteristics, fused passenger proteins are often studied without being cleaved from MBP. Here we report that a commonly used engineered MBP version (mutated to lower its surface entropy) can form interlaced dimers when fused to short protein sequences derived from the focal adhesion kinase (FAK) or the homologous protein tyrosine kinase 2 (PYK2). These MBP dimers still bind maltose and can interconvert with monomeric forms in vitro under standard conditions despite a contact surface of more than 11,000 Å2. We demonstrate that both the mutations in MBP and the fused protein sequences were required for dimer formation. The FAK and PYK2 sequences are less than 40% identical, monomeric, and did not show specific interactions with MBP, suggesting that a variety of sequences can promote this MBP dimerization. MBP dimerization was abrogated by reverting two of the eight mutations introduced in the engineered MBP. Our results provide an extreme example for induced reversible domain-swapping, with implications for protein folding dynamics. Our observations caution that passenger-promoted MBP dimerization might mislead experimental characterization of the fused protein sequences, but also suggest a simple mutation to stop this phenomenon.
Colloidal Liquid Crystals Confined to Synthetic Tactoids
Authors: Gârlea Ioana C. , Dammone Oliver , Alvarado José , Notenboom Valerie , Jia Yunfei , Koenderink Gijsje H. , Aarts Dirk G. A. L. , Lettinga M. Paul , Mulder Bela M.
Published: December 2019

When a liquid crystal forming particles are confined to a spatial volume with dimensions comparable to that of their own size, they face a complex trade-off between their global tendency to align and the local constraints imposed by the boundary conditions. This interplay may lead to a non-trivial orientational patterns that strongly depend on the geometry of the confining volume. This novel regime of liquid crystalline behavior can be probed with colloidal particles that are macro-aggregates of biomolecules. Here we study director fields of filamentous fd-viruses in quasi-2D lens-shaped chambers that mimic the shape of tactoids, the nematic droplets that form during isotropic-nematic phase separation. By varying the size and aspect ratio of the chambers we force these particles into confinements that vary from circular to extremely spindle-like shapes and observe the director field using fluorescence microscopy. In the resulting phase diagram, next to configurations predicted earlier for 3D tactoids, we find a number of novel configurations. Using Monte Carlo Simulations, we show that these novel states are metastable, yet long-lived. Their multiplicity can be explained by the co-existence of multiple dynamic relaxation pathways leading to the final stable states.
Environmental factors modulated ancient mitochondrial DNA variability and the prevalence of rheumatic diseases in the Basque Country
Authors: Laza I. M. , Hervella M. , Neira Zubieta M. , de-la-Rúa C.
Published: December 2019

Among the factors that would explain the distribution of mitochondrial lineages in Europe, climate and diseases may have played an important role. A possible explanation lies in the nature of the mitochondrion, in which the energy generation process produces reactive oxygen species that may influence the development of different diseases. The present study is focused on the medieval necropolis of San Miguel de Ereñozar (13th–16th centuries, Basque Country), whose inhabitants presented a high prevalence of rheumatic diseases and lived during the Little Ice Age (LIA). Our results indicate a close relationship between rheumatic diseases and mitochondrial haplogroup H, and specifically between spondyloarthropathies and sub-haplogroup H2. One possible explanation may be the climate change that took place in the LIA that favoured those haplogroups that were more energy-efficient, such as haplogroup H, to endure lower temperatures and food shortage. However, it had a biological trade-off: the increased risk of developing rheumatic diseases.