bluuebunny/crossref_metadata_2025 huggingface dataset:
VP55 Trial Recruitment & Retention Using Digital Tools: A Qualitative Study
Authors: Blatch-Jones Amanda , Worswick Louise , Bull Abby , Nuttall Jacqui , Griffiths Gareth , Wyatt Jeremy
Published: December 2019

Introduction

Recruitment of participants and their retention in randomized controlled trials (RCTs) is key for research efficiency. However, for many trials, recruiting and retaining participants meeting the eligible criteria is extremely challenging. Digital tools are increasingly being used to identify, recruit and retain participants. While these tools are being used, there is a lack of quality evidence to determine their value in trial recruitment.

Methods

The aim of the main study was to identify the benefits and characteristics of innovative digital recruitment and retention tools for more efficient conduct of RCTs. Here we report on the qualitative data collected on the characteristics of digital tools required by trialists, research participants, primary care staff, research funders and Clinical Trials Units (CTUs) to judge them useful. A purposive sampling strategy was used to identify 16 participants from five stakeholder groups. A theoretical framework was informed from results of a survey with UKCRC registered CTUs. Semi-structured interviews were conducted and analysed using an inductive approach. A content and thematic analysis was used to explore the stakeholder's viewpoint and the value of digital tools.

Results

The content analysis revealed that ‘barriers / challenges ‘ and ‘awareness of evidence’ were the most commonly discussed areas. Three key emergent themes were present across all groups: ‘security and legitimacy of information’, ‘inclusivity’, and ‘availability of human interaction’. Other themes focused on the engagement of stakeholders in their use and adoption of digital technology to enhance the recruitment/retention process. We also noted some interesting similarities and differences between practitioner and participant groups.

Conclusions

The key emergent themes clearly demonstrate the use of digital technology in the recruitment and retention of participants in trials. The challenge, however, is using these existing tools without sufficient evidence to support the usefulness compared to traditional techniques. This raises important questions around the potential value for future research.
VP57 Using Capital Bids For Hospital-Based Health Technology Assessment
Authors: Erskine Jamie , Chalkidou Anastasia
Published: December 2019

Introduction

The Evelina London Children's Hospital (ELCH) is undergoing a period of growth, including a new building planned to be completed within the next five years. Due to limited space and ambitions to be a state-of-the-art hospital, Horizon Scanning (HS) was considered important to ‘future-proof’ new facilities. As the aim of HS is to identify signals of coming change, ‘scanning’ the previous five years’ trends may be beneficial to an iterative HS methodology. Thus, it was thought that capital bids could provide a range of useful information required to make procurement decisions.

Methods

King's Technology Evaluation Centre (KiTEC) provided hospital-based HTA and HS support for the expansion of a London-based paediatric hospital. KiTEC focused on imaging technology due to its large spatial requirements and high-costs and assessed all capital bids made over the previous five years. A capital bidding system is used within GSTT to allocate funding for medical equipment that costs more than GBP5000 (USD 6540.70). Information was collated for all imaging equipment bid for over the previous five years and assessed for trends in imaging modalities and purchase costs.

Results

A total of 135 bids were made in the period 2013-2018, eight of which were by ECLH. Bids for ultrasound equipment were most common and rose over the period. Bids for CT scanners also rose, while bids for MRI scanners and x-ray technology were consistent and bids for fluoroscopy fell. The total cost of imaging bids over the interval rose steadily from GBP5.4 million to GBP6.9 million.

Conclusions

Due to the lifespan of imaging technology, some trends may not emerge within a five year window. While some interesting findings were made, a ten to fifteen year period may require to be scanned for a robust analysis. This methodology is best applied in an iterative fashion along with standard HS techniques.
VP62 The EUnetHTA Companion Guide: A New Repository To Support European HTA
Authors: Luhnen Miriam , Fathollah-Nejad Reza , Nocon Maya , Hutner Heike , Rehrmann Maike , Chalon Patrice , Fujita-Rohwerder Naomi
Published: December 2019

Introduction

Good quality management (QM) and the sound application of EUnetHTA's (European network for Health Technology Assessment) well-established methodology and tools are fundamental prerequisites for reliable and trustworthy joint work. To provide ultimate support and guidance to the assessment teams of EUnetHTA – and further, to ensure a sustainable mode of work for the post-2020 period – a comprehensive web-based so called “EUnetHTA Companion Guide” is established in Joint Action 3.

Methods

The Companion Guide was created using the open source Wiki software “DokuWiki”. We divided the content into five main parts: 1. EUnetHTA's QM concept, 2. QM for rapid Relative Effectiveness Assessment (REA) Pharma, 3. QM for rapid REA Other Technologies (OT) 4. Scientific Guidance & Tools and 5. QMS-related training material. The assessment processes for rapid REA Pharma and OT have been subdivided into single process steps for which the Companion Guide provides standard operating procedures (SOPs), checklists, templates, guidelines and tools. The content of the Companion Guide is continuously subjected to evaluation by means of a structured survey with regard to the achievement of its purpose of ensuring to ensure high-quality HTA reports.

Results

In May 2018, the Companion Guide was launched and is now available to all EUnetHTA partners. It provides central access to all components of the newly established QMquality management system for EUnetHTA. The user has access to training modules that provide information on how to use the Companion Guide. Moreover, the training material enables EUnetHTA partners to build up necessary capabilities for QMquality management, and application of methodologies and tools in the context of EUnetHTA.

Conclusions

The purpose of the Companion Guide is to ensure the production of high-quality HTA reports by providing ultimate support and guidance to the EUnetHTA assessment teams during their joint work. The continuous evaluation will reveal necessary revisions and the need for further developments and guidance.
VP74 Orphan Black Box: Explanatory Principles
Authors: Wang George , Macaulay Richard
Published: December 2019

Introduction

Orphan legislations over the past thirty years have successfully increased the number of drugs receiving marketing authorization for rare diseases. However, for a therapy to be accessible to most patients, it requires not only marketing authorization, but market access via public reimbursement. In many major markets, the pricing and reimbursement of new therapies is based on an assessment by a national Health Technology Assessment (HTA) body, for which economic value is typically a key consideration. This research evaluates the outcome of HTAs of orphan drugs in Europe.

Methods

HTA decision data (to 31/08/2017) was extracted from Gemeinsame Bundesausschuss (G-BA), Haute Autorité de Santé (HAS), National Institute for Health and Care Excellence (NICE), Pharmaceutical Benefits Advisory Committee (PBAC), and Scottish Medicines Consortium (SMC) websites. EC-approval data was extracted from the European Medicines Agency (to 31/08/2017).

Results

Only a small minority of drugs for orphan diseases received full recommendations for their licensed indication(s) by NICE (3/35, 9%), SMC (8/66, 12%) and PBAC (1/44, 2%). 37% (26/70) of drugs assessed received positive HTA outcome by HAS (ASMR I-III). In Germany, all approved orphan drugs (100/100) received automatic additional benefit post regulatory approval by G-BA.

Conclusions

There have been significant challenges for manufacturers in converting regulatory approval of orphan drugs into commercial success and optimised market access. Attaining positive HTA appraisals for these drugs, which have been approved under expedited regulatory pathways on a less than fully mature dataset, whilst also having high prices, due to small patient populations, limiting commercial returns, may necessitate increased utilisation of alternative reimbursement mechanisms.
VP82 Impact of Evidence Synthesis Methods on Outcome of Economic Evaluation
Authors: Gorry Claire , Leahy Joy , Lamrock Felicity , Walsh Cathal , White Arthur , Barry Michael , McCullagh Laura
Published: December 2019

Introduction

Evidence synthesis (ES) is often required for economic evaluation (EE) of pharmaceuticals. Commonly used methods are based on the assumption of proportional hazards in trial data, using the hazard ratio (HR). Alternative methods for ES are increasingly used in EE, in situations where the pattern of hazards in the trial data indicates that the proportional hazards assumption may be violated. The impact of these methodological choices on model outcomes is explored.

Methods

A network of trials of BRAF-targeted treatments for advanced melanoma, derived using a systematic review of the literature, is chosen for the study. Guyot's method is used to create individual-patient Kaplan-Meier (K-M) data from published survival curves. Log-cumulative hazard plots and Schoenfeld residuals are derived to examine patterns in hazards within the trial data. All analyses are conducted in R version 3.5.0©. Three alternative methods for ES are tested: 1) Network meta-analysis (NMA) based on published HRs and the assumption of proportional hazards. 2) NMA using fractional polynomials (FP) based on digitised K-M data, allowing the relaxation of the proportional hazards assumption. 3) NMA using an accelerated failure time (AFT) model based on digitised K-M data, allowing the relaxation of the proportional hazards assumption. The derived estimates of relative efficacy from each method are applied in a partitioned survival cost-effectiveness model programmed in Microsoft Excel™.

Results

The model outcomes predicted by each method (HR, FP and AFT) are presented and compared. Both deterministic and probabilistic results are presented, alongside a discussion around how the uncertainty in these structural assumptions may be captured in EE.

Conclusions

Structural assumptions in ES may lead to differences in model outcomes. The impact of these differences may be important in situations where decision uncertainty is high. Methods should be chosen and justified based on patterns of hazard present in the trial data.
VP89 A Preliminary Equity Checklist To Support The HTA Process
Authors: Benkhalti Maria , Dagenais Pierre
Published: December 2019

Introduction

There is increased recognition of the need to include equity considerations in HTA. Despite this, a recent World Health Organization report has found that this is seldom the case. We developed a preliminary version of an equity checklist in the hopes that tangible guidance will increase such analyses in the future and contribute to smart capability building.

Methods

The checklist is based on the Equity Framework for HTA developed by Culyer & Bombard (2012). The elements presented in the framework were revised to follow the stepwise HTA process. A comprehensive literature search was used to update and complete the elements. The checklist was then piloted in an HTA in 2018 and subsequently further refined through a workshop during a national HTA conference in Canada.

Results

These steps resulted in a 27-item checklist leading to consider different aspects of the three major phases in the HTA process. The scoping phase brings questions relative to defining and contextualizing equity, such as highlighting potential minority groups and including vulnerability factors in the logic model. The development phase leads methodological approaches facilitating the analysis of inequities as well as considering contextual realities leading to inequities. The last phase, drafting of recommendations, aims to be aware of the evidence synthesis approaches as well as the various aspects to ensure recommendations consider existing inequities and avoid contributing to their development.

Conclusions

Given the essence of HTA to protect health by ensuring optimal technologies and interventions are adopted to the benefit of all system users, the consideration of inequities should constitute an integral part of its process. The use of a pragmatic and simple checklist to aid the planning of an HTA could contribute to greater consideration of inequities in the future. A movement in this direction could also lead to greater methodological developments for health equity analysis in HTA.
VP100 Ultraradical Ovarian Cancer Surgery Comparative Clinical Effectiveness
Authors: Cummins Carole , Patrick Hannah , Long Joanna , Kumar Satyam , Sundar Sudha , Bramley George
Published: December 2019

Introduction

Ovarian Cancer is usually diagnosed at an advanced stage. Extensive or ultra-radical surgery aims to improve the outcome by removing all visible tumour. National Institute for Health and Care Excellence UK 2013 Guidance expressed concern about its efficacy and safety, recommending research comparing complication rates, survival and quality of life with those following standard surgery. We present prospective observational data on quality of life and survival following surgery for advanced ovarian cancer. Innovative methods were used to collect patient reported outcomes and complex surgical information to compare outcomes of surgery of greater or lesser complexity used in routine practice.

Methods

A cohort study collected disease, surgical, complications, survival and quality of life data (validated instruments including EURO-QOL, EORTC-30 and OVA28) across a 2-year period in 12 United Kingdom sites and in parallel studies in Melbourne, Australia and Kolkata, India.

Results

Two hundred and sixty patients undergoing cytoreductive surgery were recruited in 12 months. Centres varied in utilisation of complex surgical procedures. Excluding patients with inoperable disease, 125 patients underwent low, 70 intermediate and 63 high Surgical Complexity Score (SCS) procedures. Complete cytoreduction with < 1cm residual disease was achieved in 100/125 (80 percent) low, 65/70 (92 percent) intermediate, and 57/63 (90 percent) high SCS groups (p = 0.023). Compliance with 12 months questionnaires was 89%. All surgical groups had improved EORTC QLC 30 Global at 12 months compared with prior to operation, with overlapping 95% confidence intervals and no between group differences at 12 months. Complications, survival and quality of life adjusted for disease burden and surgical complexity over 2 years’ follow-up will be described.

Conclusions

Results will inform the update of NICE Interventional Procedures guidance recommendations on clinical governance arrangements for ovarian cancer surgery and enable clinicians and patients to better understand the outcomes of surgery, informing the consent process.
The Welsh Church Act 1914: A Century of Constitutional Freedom for the Church in Wales?
Authors: Doe Norman
Published: December 2019

The approach of the centenary of the disestablishment of the Church of England in Wales offers a good opportunity to reflect on legal aspects of the life of the Church in Wales since 1920. Religious equality had been the principal stimulus for the Welsh Church Act 1914. This statute, together with the release of the Welsh dioceses by the Archbishop of Canterbury to form a separate Anglican province, necessitated the formulation of a constitution for the Church. Innovation was avoided, and continuity protected. ‘Vestiges of establishment’ continued, in burial and marriage, as the result of political expediency. The original structure of the Constitution continues to this day – a complex of various instruments. Change has been piecemeal. The Church still has no modernised body of canon law and its soft law has increased dramatically. However, understandings about the purposes of the Constitution have changed, and the demand for constitutional change has quickened recently, particularly since the Harries Review of the Church in Wales in 2012.
General Synod of the Church of Ireland
Authors: Turner Cate
Published: December 2019

This year's General Synod, the second meeting of the triennium, was held for the first time in the Diocese of Derry and Raphoe. The venue was the Millennium Forum Theatre in the centre of the historic walled city of Derry/Londonderry and a civic reception was held at the Guildhall, hosted by the mayor of Derry City and Strabane District. The Synod considered Bills relating to Holy Communion by extension; liturgical provision for miscarriage, stillbirth and neonatal death; and diocesan boundaries.
Enhancing ENSO Prediction Skill by Combining Model‐Analog and Linear Inverse Models (MA‐LIM)
Authors: Shin Jihoon , Park Sungsu , Shin Sang‐Ik , Newman Matthew , Alexander Michael A.
Published: December 2019

To enhance El Niño–Southern Oscillation (ENSO) forecast skill, we devise a model analog (MA)‐linear inverse model (LIM) by nudging sea surface temperature and sea surface height anomalies forecasted by the LIM into the MA. The performances of the LIM, MA, and MA‐LIM are compared to general circulation model simulations and observations. At short (long) lead month
, the LIM (MA) predicts the Niño 3.4 SST anomalies better than the MA (LIM). On the other hand, the MA‐LIM shows the best performance at all
. At
, the MA performs better than the LIM in the eastern equatorial Pacific and Indian Oceans but worse in other regions. The MA‐LIM substantially remedies the undesirable aspects of the MA. The success of the MA‐LIM appears to come from the use of more accurate initial conditions than the MA and an ad hoc implementation of seasonal cycle and nonlinearities into the LIM through nudging to the MA.
Emission of Electrostatic Whistler Waves Associated With Weak Electron‐Beam Excited Langmuir Waves: The 2‐D Particle‐in‐Cell Simulations
Authors: Sun Haomin , Sun Jicheng
Published: December 2019

In this paper, we perform two‐dimensional (2‐D) electrostatic particle‐in‐cell simulations to investigate the emission of electrostatic whistler waves (EWWs) associated with the weak electron‐beam excited Langmuir waves. Both the linear theory and simulations have shown that quasi‐parallel Langmuir waves can be generated during the linear stage of the beam‐plasma interaction process. The 2‐D particle‐in‐cell simulations further demonstrated that when the background magnetic field is strong (Ωe/ωpe > 1, where Ωe and ωpe are electron gyrofrequency and electron plasma frequency, respectively), EWWs will be generated in weak electron‐beam excited Langmuir waves during the nonlinear stage of wave growth, leading to the increment of perpendicular electric field. When the background magnetic field is weak (Ωe/ωpe < 1), EWWs cannot be generated during the nonlinear stage and the perpendicular electric field has no obvious nonlinear increment. In addition, the influences of the electron beam density and the electron beam velocity on the generation of EWWs are also analyzed in this paper. The simulation results may also account for observations in the Earth's Auroral region.
Nutraceuticals, antioxidant pigments, and phytochemicals in the leaves of Amaranthus spinosus and Amaranthus viridis weedy species
Authors: Sarker Umakanta , Oba Shinya
Published: December 2019

Six selected weedy Amaranthus genotypes (three accessions from each species of A. viridis and A. spinosus) were evaluated in terms of nutrients, minerals, antioxidant constituents and antioxidant activity for the possibilities of weedy species as a vegetable cultivar in a randomized complete block design with three replications. As leafy vegetable, Weedy Amaranthus has remarkable protein, dietary fiber, carbohydrates, Ca, K, Mg, P, S, Fe, Mn, Cu, Zn, Na, Mo, B, chlorophylls, β-cyanins, β-xanthins, betalains, β-carotene, vitamin C, TPC, TFC, and TAC (DPPH and ABTS+) compared to any cultivated species. The A. viridis genotype WAV7 and A. spinosus genotype WAS13 had the highest nutrients, pigments, vitamins, phenolics, flavonoids, and antioxidant. Hence, these two weedy accessions could be used as an antioxidant profile enriched cultivar with high nutritional and antioxidant activity. Pigments, β-carotene, vitamin C, phenolics, and flavonoids had strong antioxidant activity and played a vital role in the antioxidant activity of weedy Amaranthus genotypes. Weedy species are an excellent source of phenolics, flavonoids, and antioxidants that have many pharmacological and medicinal effects of their traditional applications and detoxify ROS and offered huge prospects for feeding the antioxidant-deficient community to cope with the hidden hunger and attaining nutritional and antioxidant sufficiency.
Peculiarities of pseudogap in Y0.95Pr0.05Ba2Cu3O7−δ single crystals under pressure up to 1.7 GPa
Authors: Solovjov A. L. , Omelchenko L. V. , Petrenko E. V. , Vovk R. V. , Khotkevych V. V. , Chroneos A.
Published: December 2019

The effect of hydrostatic pressure up to P = 1.7 GPa on the fluctuation conductivity σ′(T) and pseudogap ∆*(T) in Y0.95Pr0.05Ba2Cu3O7−δ single crystal with critical temperature Тс = 85.2 K (at P = 0) was investigated. The application of pressure leads to the increase in Tc with dTc/dP = +1.82 K∙GPa−1 while the resistance decreases as dlnρ(100 K)/dP = −(10.5 ± 0.2) %∙GPa−1. Regardless of the pressure, in the temperature interval from Tc to T0 (~88 K at P = 0) the behaviour of σ′(T) is well described by the Aslamazov – Larkin (AL – 3D) fluctuation theory, and above the T0 by the Lawrence – Doniach theory (LD). The Maki-Thompson (MT – 2D) fluctuation contribution is not observed. This indicates the presence of structural defects in the sample induced by Pr. Here it is determined for the first time that when the pressure is applied to the Y1−xPrxBa2Cu3O7−δ single crystal, the pseudogap increases as dlnΔ*/dP = 0.17 GPa–1.
High heritability of coral calcification rates and evolutionary potential under ocean acidification
Authors: Jury Christopher P. , Delano Mia N. , Toonen Robert J.
Published: December 2019

Estimates of heritability inform evolutionary potential and the likely outcome of many management actions, but such estimates remain scarce for marine organisms. Here, we report high heritability of calcification rate among the eight most dominant Hawaiian coral species under reduced pH simulating future ocean conditions. Coral colonies were sampled from up to six locations across a natural mosaic in seawater chemistry throughout Hawaiʻi and fragmented into clonal replicates maintained under both ambient and high pCO2 conditions. Broad sense heritability of calcification rates was high among all eight species, ranging from a low of 0.32 in Porites evermanni to a high of 0.61 in Porites compressa. The overall results were inconsistent with short-term acclimatization to the local environment or adaptation to the mean or ideal conditions. Similarly, in ‘local vs. foreign’ and ‘home vs. away’ tests there was no clear signature of local adaptation. Instead, the data are most consistent with a protected polymorphism as the mechanism which maintains differential pH tolerance within the populations. Substantial individual variation, coupled with high heritability and large population sizes, imply considerable scope for natural selection and adaptive capacity, which has major implications for evolutionary potential and management of corals in response to climate change.
Risk of yellow fever virus importation into the United States from Brazil, outbreak years 2016–2017 and 2017–2018
Authors: Dorigatti Ilaria , Morrison Stephanie , Donnelly Christl A. , Garske Tini , Bowden Sarah , Grills Ardath
Published: December 2019

Southeast Brazil has experienced two large yellow fever (YF) outbreaks since 2016. While the 2016–2017 outbreak mainly affected the states of Espírito Santo and Minas Gerais, the 2017–2018 YF outbreak primarily involved the states of Minas Gerais, São Paulo, and Rio de Janeiro, the latter two of which are highly populated and popular destinations for international travelers. This analysis quantifies the risk of YF virus (YFV) infected travelers arriving in the United States via air travel from Brazil, including both incoming Brazilian travelers and returning US travelers. We assumed that US travelers were subject to the same daily risk of YF infection as Brazilian residents. During both YF outbreaks in Southeast Brazil, three international airports—Miami, New York-John F. Kennedy, and Orlando—had the highest risk of receiving a traveler infected with YFV. Most of the risk was observed among incoming Brazilian travelers. Overall, we found low risk of YFV introduction into the United States during the 2016–2017 and 2017–2018 outbreaks. Decision makers can use these results to employ the most efficient and least restrictive actions and interventions.
Effects of Chikungunya virus immunity on Mayaro virus disease and epidemic potential
Authors: Webb Emily M. , Azar Sasha R. , Haller Sherry L. , Langsjoen Rose M. , Cuthbert Candace E. , Ramjag Anushka T. , Luo Huanle , Plante Kenneth , Wang Tian , Simmons Graham , Carrington Christine V. F. , Weaver Scott C. , Rossi Shannan L. , Auguste Albert J.
Published: December 2019

Mayaro virus (MAYV) causes an acute febrile illness similar to that produced by chikungunya virus (CHIKV), an evolutionary relative in the Semliki Forest virus complex of alphaviruses. MAYV emergence is typically sporadic, but recent isolations and outbreaks indicate that the virus remains a public health concern. Given the close phylogenetic and antigenic relationship between CHIKV and MAYV, and widespread distribution of CHIKV, we hypothesized that prior CHIKV immunity may affect MAYV pathogenesis and/or influence its emergence potential. We pre-exposed immunocompetent C57BL/6 and immunocompromised A129 or IFNAR mice to wild-type CHIKV, two CHIKV vaccines, or a live-attenuated MAYV vaccine, and challenged with MAYV. We observed strong cross-protection against MAYV for mice pre-exposed to wild-type CHIKV, and moderately but significantly reduced cross-protection from CHIKV-vaccinated animals. Immunity to other alphavirus or flavivirus controls provided no protection against MAYV disease or viremia. Mechanistic studies suggested that neutralizing antibodies alone can mediate this protection, with T-cells having no significant effect on diminishing disease. Finally, human sera obtained from naturally acquired CHIKV infection cross-neutralized MAYV at high titersin vitro. Altogether, our data suggest that CHIKV infection can confer cross-protective effects against MAYV, and the resultant reduction in viremia may limit the emergence potential of MAYV.
Characterization of the complete chloroplast genome sequence of Dalbergia species and its phylogenetic implications
Authors: Song Yun , Zhang Yongjiang , Xu Jin , Li Weimin , Li MingFu
Published: December 2019

The pantropical plant genus Dalbergia comprises approximately 250 species, most of which have a high economic and ecological value. However, these species are among the most threatened due to illegal logging and the timber trade. To enforce protective legislation and ensure effective conservation of Dalbergia species, the identity of wood being traded must be accurately validated. For the rapid and accurate identification of Dalbergia species and assessment of phylogenetic relationships, it would be highly desirable to develop more effective DNA barcodes for these species. In this study, we sequenced and compared the chloroplast genomes of nine species of Dalbergia. We found that these chloroplast genomes were conserved with respect to genome size, structure, and gene content and showed low sequence divergence. We identified eight mutation hotspots, namely, six intergenic spacer regions (trnL-trnT, atpA-trnG, rps16-accD, petG-psaJ, ndhF-trnL, and ndhG-ndhI) and two coding regions (ycf1a and ycf1b), as candidate DNA barcodes for Dalbergia. Phylogenetic analyses based on whole chloroplast genome data provided the best resolution of Dalbergia, and phylogenetic analysis of the Fabaceae showed that Dalbergia was sister to Arachis. Based on comparison of chloroplast genomes, we identified a set of highly variable markers that can be developed as specific DNA barcodes.
Molecular Geometry Prediction using a Deep Generative Graph Neural Network
Authors: Mansimov Elman , Mahmood Omar , Kang Seokho , Cho Kyunghyun
Published: December 2019

A molecule’s geometry, also known as conformation, is one of a molecule’s most important properties, determining the reactions it participates in, the bonds it forms, and the interactions it has with other molecules. Conventional conformation generation methods minimize hand-designed molecular force field energy functions that are often not well correlated with the true energy function of a molecule observed in nature. They generate geometrically diverse sets of conformations, some of which are very similar to the lowest-energy conformations and others of which are very different. In this paper, we propose a conditional deep generative graph neural network that learns an energy function by directly learning to generate molecular conformations that are energetically favorable and more likely to be observed experimentally in data-driven manner. On three large-scale datasets containing small molecules, we show that our method generates a set of conformations that on average is far more likely to be close to the corresponding reference conformations than are those obtained from conventional force field methods. Our method maintains geometrical diversity by generating conformations that are not too similar to each other, and is also computationally faster. We also show that our method can be used to provide initial coordinates for conventional force field methods. On one of the evaluated datasets we show that this combination allows us to combine the best of both methods, yielding generated conformations that are on average close to reference conformations with some very similar to reference conformations.
Screening history and FIGO-stages among Danish women with cervical cancer in 2012–2014: a register-based study
Authors: Bchtawi Abir Khalil , Saritas Sinem , Schledermann Doris , Christensen René dePont , Jochumsen Kirsten Marie
Published: December 2019

The objective was to examine whether attendance in the mass cervical screening programme has implications for the prognosis when cervical cancer is diagnosed. We performed a retrospective analysis of all cases of cervical cancer between 1st of January 2012 and 31st of December 2014 in the Region of Southern Denmark. The cases were retrieved from the Danish National Pathology Registry, PatoBank. Odds ratios (OR) with confidence intervals (95% CI) were calculated for attendees versus non-attendees of the screening programme by using χ2-test. 216 patients were included in the study. 61.6% of the study population had not attended the screening programme. Patients who had attended the programme were characterised by disease in low stage (OR = 3.14, 95% CI; 1.66 to 5.92), treatment with surgery alone (OR = 2.63, 95% CI; 1.49 to 4.64) and a lower risk of death (OR = 0.36, 95% CI; 0.15 to 0.87). Adenocarcinomas were more often detected among attendees of the programme compared to squamous cell carcinomas (OR = 4.06, 95% CI; 2.03 to 8.14). Statistically significant results regarding relapse of cancer (OR = 0.62, 95% CI; 0.23 to 1.68, p = 0.47) and lymph node metastases (OR = 0.62, 95% CI; 0.32 to 1.21, p = 0.19) were not found. Cervical cancer detected in women who had attended the mass cervical screening programme prior to the diagnosis, was shown to have a statistically significant lower FIGO stage (p = 0.0004) and was therefore linked to less extensive treatment options. Continued focus on increasing the participation rate of the programme is of importance, as the nonattendance rate continues to be high.
Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background
Authors: Falcone Sara , Wisby Laura , Nicol Thomas , Blease Andrew , Starbuck Becky , Parker Andrew , Sanderson Jeremy , Brown Steve D. M. , Scudamore Cheryl L. , Pusey Charles D. , Tam Frederick W. K. , Potter Paul K.
Published: December 2019

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modified genetically. We have identified a point mutation in Col4a4 in mice where disease is modified by strain background, providing further evidence of the genetic modification of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identified early differences in disease progression, including expression of podocyte-specific genes and podocyte morphology. In C57BL/6J mice podocyte effacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We find that there is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.
Regulatory Role of PlaR (YiaJ) for Plant Utilization in Escherichia coli K-12
Authors: Shimada Tomohiro , Yokoyama Yui , Anzai Takumi , Yamamoto Kaneyoshi , Ishihama Akira
Published: December 2019

Outside a warm-blooded animal host, the enterobacterium Escherichia coli K-12 is also able to grow and survive in stressful nature. The major organic substance in nature is plant, but the genetic system of E. coli how to utilize plant-derived materials as nutrients is poorly understood. Here we describe the set of regulatory targets for uncharacterized IclR-family transcription factor YiaJ on the E. coli genome, using gSELEX screening system. Among a total of 18 high-affinity binding targets of YiaJ, the major regulatory target was identified to be the yiaLMNOPQRS operon for utilization of ascorbate from fruits and galacturonate from plant pectin. The targets of YiaJ also include the genes involved in the utilization for other plant-derived materials as nutrients such as fructose, sorbitol, glycerol and fructoselysine. Detailed in vitro and in vivo analyses suggest that L-ascorbate and α-D-galacturonate are the effector ligands for regulation of YiaJ function. These findings altogether indicate that YiaJ plays a major regulatory role in expression of a set of the genes for the utilization of plant-derived materials as nutrients for survival. PlaR was also suggested to play protecting roles of E. coli under stressful environments in nature, including the formation of biofilm. We then propose renaming YiaJ to PlaR (regulator of plant utilization).
The chick pallium displays divergent expression patterns of chick orthologues of mammalian neocortical deep layer-specific genes
Authors: Fujita Toshiyuki , Aoki Naoya , Fujita Eiko , Matsushima Toshiya , Homma Koichi J. , Yamaguchi Shinji
Published: December 2019

The avian pallium is organised into clusters of neurons and does not have layered structures such as those seen in the mammalian neocortex. The evolutionary relationship between sub-regions of avian pallium and layers of mammalian neocortex remains unclear. One hypothesis, based on the similarities in neural connections of the motor output neurons that project to sub-pallial targets, proposed the cell-type homology between brainstem projection neurons in neocortex layers 5 or 6 (L5/6) and those in the avian arcopallium. Recent studies have suggested that gene expression patterns are associated with neural connection patterns, which supports the cell-type homology hypothesis. However, a limited number of genes were used in these studies. Here, we showed that chick orthologues of mammalian L5/6-specific genes, nuclear receptor subfamily 4 group A member 2 and connective tissue growth factor, were strongly expressed in the arcopallium. However, other chick orthologues of L5/6-specific genes were primarily expressed in regions other than the arcopallium. Our results do not fully support the cell-type homology hypothesis. This suggests that the cell types of brainstem projection neurons are not conserved between the avian arcopallium and the mammalian neocortex L5/6. Our findings may help understand the evolution of pallium between birds and mammals.
Publisher Correction: Self-harm behaviour and externally-directed aggression in psychiatric outpatients: a multicentre, prospective study (viormed-2 study)
Authors: Scocco Paolo , Macis Ambra , Ferrari Clarissa , Bava Mattia , Bianconi Giorgio , Bulgari Viola , Candini Valentina , Carrà Giuseppe , Cavalera Cesare , Clerici Massimo , Conte Giovanni , Cricelli Marta , Ferla Maria Teresa , Iozzino Laura , Stefana Alberto , de Girolamo Giovanni
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Ginsenoside Rb1 exerts antiarrhythmic effects by inhibiting INa and ICaL in rabbit ventricular myocytes
Authors: Liu Zhipei , Song Lv , Zhang Peipei , Cao Zhenzhen , Hao Jie , Tian Youjia , Luo Antao , Zhang Peihua , Ma Jihua
Published: December 2019

Ginsenoside Rb1 exerts its pharmacological action by regulating sodium, potassium and calcium ion channels in the membranes of nerve cells. These ion channels are also present in cardiomyocytes, but no studies have been reported to date regarding the effects of Rb1 on cardiac sodium currents (INa), L-type calcium currents (ICaL) and action potentials (APs). Additionally, the antiarrhythmic potential of Rb1 has not been assessed. In this study, we used a whole-cell patch clamp technique to assess the effect of Rb1 on these ion channels. The results showed that Rb1 inhibited INa and ICaL, reduced the action potential amplitude (APA) and maximum upstroke velocity (Vmax), and shortened the action potential duration (APD) in a concentration-dependent manner but had no effect on the inward rectifier potassium current (IK1), delayed rectifier potassium current (IK) or resting membrane potential (RMP). We also designed a pathological model at the cellular and organ level to verify the role of Rb1. The results showed that Rb1 abolished high calcium-induced delayed afterdepolarizations (DADs), depressed the increase in intracellular calcium ([Ca2+]i), relieved calcium overload and protected cardiomyocytes. Rb1 can also reduce the occurrence of ventricular premature beats (VPBs) and ventricular tachycardia (VT) in ischemia-reperfusion (I-R) injury.
Intra-articular injection of indomethacin–methotrexate in situ hydrogel for the synergistic treatment of rheumatoid arthritis
Authors: Yin Na , Guo Xueting , Sun Rong , Liu Hongbing , Tang Lihua , Gou Jingxin , Yin Tian , He Haibing , Zhang Yu , Tang Xing
Published: December 2019

Intra-articular injection of a temperature-sensitive hydrogel containing D-NPs formed by PEI-SS and IND and MTX.
Physical parameters of selected Gaia mass asteroids
Authors: Podlewska-Gaca E. , Marciniak A. , Alí-Lagoa V. , Bartczak P. , Müller T. G. , Szakáts R. , Duffard R. , Molnár L. , Pál A. , Butkiewicz-Bąk M. , Dudziński G. , Dziadura K. , Antonini P. , Asenjo V. , Audejean M. , Benkhaldoun Z. , Behrend R. , Bernasconi L. , Bosch J. M. , Chapman A. , Dintinjana B. , Farkas A. , Ferrais M. , Geier S. , Grice J. , Hirsh R. , Jacquinot H. , Jehin E. , Jones A. , Molina D. , Morales N. , Parley N. , Poncy R. , Roy R. , Santana-Ros T. , Seli B. , Sobkowiak K. , Verebélyi E. , Żukowski K.
Published: December 2019

Context. Thanks to the Gaia mission, it will be possible to determine the masses of approximately hundreds of large main belt asteroids with very good precision. We currently have diameter estimates for all of them that can be used to compute their volume and hence their density. However, some of those diameters are still based on simple thermal models, which can occasionally lead to volume uncertainties as high as 20–30%.

Aims. The aim of this paper is to determine the 3D shape models and compute the volumes for 13 main belt asteroids that were selected from those targets for which Gaia will provide the mass with an accuracy of better than 10%.

Methods. We used the genetic Shaping Asteroids with Genetic Evolution (SAGE) algorithm to fit disk-integrated, dense photometric lightcurves and obtain detailed asteroid shape models. These models were scaled by fitting them to available stellar occultation and/or thermal infrared observations.

Results. We determine the spin and shape models for 13 main belt asteroids using the SAGE algorithm. Occultation fitting enables us to confirm main shape features and the spin state, while thermophysical modeling leads to more precise diameters as well as estimates of thermal inertia values.

Conclusions. We calculated the volume of our sample of main-belt asteroids for which the Gaia satellite will provide precise mass determinations. From our volumes, it will then be possible to more accurately compute the bulk density, which is a fundamental physical property needed to understand the formation and evolution processes of small Solar System bodies.
Crestal Bone Changes in Different Implants Designs: A Prospective Clinical Trial
Authors: Caetano Gustavo M. , Pauletto Patrícia , Mezzomo Luis A. , Rivaldo Elken G.
Published: December 2019

Objective Several modifications, such as changes in the implant–abutment connection, have been suggested in studies on dental implants to better preserve the peri-implant bone level. The aim of this study was to prospectively compare crestal bone level changes between two different implant designs—tissue level (TL) and bone level (BL).

Materials and Methods The sample comprised 18 patients, on whom a total of 30 hydrophilic tissue- and bone level implants were placed (SLActive, Straumann Institut AG, Basel, Switzerland), in the posterior region of the maxilla or the mandible. Impressions were taken after 45 days of healing. Then, cemented-retained metalloceramic crowns were fabricated and installed. Marginal bone level changes were assessed by the paralleling technique of periapical radiographies, on both mesial and distal aspects of each implant, at the moment of the implant placement and after 1 year of loading. Photoshop software was used to perform linear measurements by a single and calibrated examiner.

Statistical Analysis The Mann–Whitney test at a 5% significance level was used to compare the bone changes among the implants assessed.

Results A significantly lower (p = 0.048) bone remodeling was observed on bone level implants (0.05 mm), when compared to tissue level implants (0.47 mm; p = 0.048). The average marginal bone level changes at the distal aspect did not show any statistically significant difference (p = 0.325).

Conclusions Tissue level implants presented greater bone loss in the mesial surface than bone level implants. Both designs presented stable and clinically acceptable bone crests.
In Vivo Evaluation of Operative Torque Generated by Two Nickel-Titanium Rotary Instruments during Root Canal Preparation
Authors: Gambarini Gianluca , Galli Massimo , Seracchiani Marco , Di Nardo Dario , Versiani Marco A. , Piasecki Lucila , Testarelli Luca
Published: December 2019

Objectives This in vivo study evaluated the operative torque and preparation time of ProTaper NEXT (Dentsply Maillefer; Ballaigues, Switzerland) and EdgeFile X7 (EdgeEndo; Albuquerque, New Mexico, United States) rotary systems during root canal preparation of maxillary premolars.

Materials and Methods Ten double-rooted maxillary premolars with independent canals were selected. Each canal in each tooth was prepared with one of the rotary systems (n = 10), ProTaper NEXT or EdgeFile X7. The instruments were rotated at 300 rpm with maximum torque set at 2 N.cm using an electric motor (KaVo; Biberach, Germany) that automatically recorded torque values at every 1/10th of a second (ds).

Statistical Analysis Operative torque (N.cm) and preparation time (s) of the first shaping instrument (size 17/.04) of both rotary systems were recorded and statistically compared using the Mann–Whiney U test with a significance level set at 5%.

Results No instrument exhibited flute deformation or underwent intracanal failure. No differences were found between the instruments regarding the maximum (peak) torque values (p > 0.05). EdgeFile X7 17/.04 required significantly less preparation time (3.75 seconds interquartile range [IQR]: 3.2–9.0) than ProTaper NEXT X1 (15.45 seconds IQR: 8.35–21.1) (p < 0.05). The median operative torque values of ProTaper NEXT X1 (0.26 N.cm; IQR: 0.18–0.49) were significantly higher compared with EdgeFile X7 17/.04 (0.09 N.cm; IQR: 0.05–0.17) (p < 0.05).

Conclusions Although no difference was found between the median peak torque values of ProTaper NEXT X1 and EdgeFile X7 17/.04 instruments, the operative torque and instrumentation time results were impacted by their different designs and alloys during clinical preparation of root canals.
Technical Quality of Root Canal Filling in Preclinical Training at Strasbourg University Using Two Teaching Protocols
Authors: Kharouf Naji , Hemmerlé Joseph , Haikel Youssef , Mancino Davide
Published: December 2019

Objectives The aim of this study was to compare two teaching protocols according to the technical quality of root canal therapy (RCT) and the procedural errors occurred in preclinical training.

Materials and Methods Two different groups of students were concerned. The first one (G1) performed a crown-down technique to shape the root canal systems and cold lateral condensation technique to fill them. The second one (G2) performed a step-down technique without initial manual scouting to shape the root canal systems, and cold hydraulic condensation technique, to fill them. G2 used clinical operative microscope to check the access cavity preparation.

Statistical Analysis The quality of RCTs and procedural errors were recorded and analyzed using chi-squared test and t-test.

Results Four hundred sixty-eight root canals from 152 maxillary molars were treated by the G1 students: 46.6% canals were judged as acceptable. Four hundred sixty-nine root canals from 152 mandibular molars were treated by G1: 58.8% canals were judged as acceptable. Five hundred fifteen root canals from 156 maxillary molars were treated by G2 students: 84.1% canals were judged as acceptable. Four hundred ninety-three root canals from 156 mandibular molars were treated by G2: 90.9% canals were judged as acceptable. Among the errors, the incidence of “ledges” and “fractured instruments” was statistically significant in G1 compared with G2, both on maxillary and on mandibular molars.

Conclusions The molar RCTs performed by G2, who got benefit from the new teaching protocol, resulted in a better quality of root filling and in fewer procedural errors compared with the molar RCTs performed by G1.