bluuebunny/crossref_metadata_2025 huggingface dataset:
OP50 IQWiG And GRADE – An Exemplary Comparison Of Methods
Authors: Schell Lisa , Sauerland Stefan , Thomas Stefanie , Kaiser Thomas , Luhnen Miriam , Lietz Martina , Skipka Guido
Published: December 2019

Introduction

Efforts to harmonize health technology assessment (HTA) processes and methods across Europe are currently intensified. In this context, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach has been proposed as a “common ground” in joint HTAs. However, GRADE has been primarily developed to support authors of clinical guidelines. Therefore, it is unclear whether HTA reports based on GRADE are compatible with the methods currently applied by European HTA organizations.

Methods

We contrasted IQWiG's methods paper and publications by the GRADE Working Group with regard to the following domains: 1) risk of bias (RoB) assessment 2) prerequisites for “greater benefit” (assuming that IQWiG's “greater benefit” corresponds to a GRADE assessment of at least low certainty and a small important effect) and 3) consideration of non-randomized studies (NRS). We present illustrative differences and highlight similarities.

Results

Overall, RoB assessments are very similar under both approaches. However, we identified several important differences. In case of very severe publication bias, IQWiG methods preclude drawing a conclusion, whereas GRADE requires only downgrading the certainty of evidence while still allowing for a conclusion on effect sizes. Secondly, IQWiG generally requires a statistically significant effect for a “greater benefit”, while GRADE does not (statistically non-significant effects would only necessitate downgrading the certainty of results for imprecision). Another difference is that in general, NRS are not included in IQWiG assessments when randomized studies (RS) are available and thus possible. In contrast, preliminary GRADE guidance recommends considering NRS in addition to RS when the RS evidence is of low or very low certainty.

Conclusions

While GRADE and IQWiG's method share some similarities, our exemplary analysis shows that there are some notable differences. Therefore, GRADE should not be used “out of the box” for European HTAs. To foster further discussion, more research (including a comprehensive comparison of methods and an analysis of resources for adaptation) is needed.
OP69 Initiatives To Improve The Timeliness Of Cancer Diagnosis
Authors: Pollock Michelle , Craig Rodger , Chojecki Dagmara , Guo Bing
Published: December 2019

Introduction

Conventional wisdom suggests that accelerating the speed of cancer diagnosis should improve health outcomes. However, cancer diagnosis requires complex coordination and effective communication between care providers working across many areas of the healthcare system. Since 2000, several nations and jurisdictions have aimed to improve timeliness of cancer diagnosis by integrating and coordinating cancer diagnostic services for patients. The objective of this study was to describe the impact of these existing initiatives.

Methods

We conducted an environmental scan consisting of a literature review (published academic and grey literature) and key informant consultations (online surveys and telephone interviews with experts who have knowledge of existing initiatives). We searched for initiatives in the United Kingdom, the Nordic countries, Canada, Australia, and New Zealand. For each initiative, we extracted data on their development and implementation, structure and functioning, intended outcomes and effectiveness, costs and cost savings, and enablers and barriers.

Results

Eighty-nine relevant documents and 20 key informants contributed to this study. We identified 21 relevant initiatives, including seven national initiatives targeting multiple types of cancer. The literature review found that most initiatives accelerated the diagnostic phase of cancer care by several days or weeks. These wait time reductions were often associated with improved patient experience, but not less advanced cancer stage or increased long-term survival. Insights from key informants improved our understanding of the costs, enablers, and barriers associated with program implementation and maintenance.

Conclusions

These results can be used as a first step to inform the development, evaluation, and improvement of international cancer diagnostic pathways. Stakeholders wishing to accelerate cancer diagnosis should consider the feasibility of achieving their intended program outcomes based on the existing research evidence, desired type of initiative, and jurisdiction's unique contextual factors.
OP105 Factors Affecting Horizon Scanning For Hospital-Based Health Technology Assessment
Authors: Chalkidou Anastasia , Erskine Jamie , Macmillan Thomas , Keevil Stephen
Published: December 2019

Introduction

The strategic MedTech investment for the expansion of a central London paediatric hospital must sustain its ambitions to remain a state-of-the-art hospital, whilst implementing recent and future MedTech innovations and taking into account spatial and financial limitations. Horizon scanning (HS) is an important health technology assessment (HTA) tool to achieve these goals. To this end, we developed a methodology to help decide the suitability of investing in the following imaging-based MedTech: a hybrid theatre incorporating a biplane, intra-operative MRI (iMRI), multi-detector computed tomography (CT) scanners, and an EOS imaging system and predict the complementary technologies required for the decade to come. These technologies not only require adequate spatial resources but a significant upfront capital investment.

Methods

Three sources of information were used: i) a literature search, selected journals and other horizon scanning resources that examined current efficiency, safety, and cost-effectiveness for the proposed technologies, ii) expert elicitation in the form of user-group meetings and one-to-one discussions with clinical and service management teams and iii) hospital data consisting of audit and information from capital equipment bids.

Results

With the exception of limited comparative data on iMRI (mainly including adults), little evidence exists to support investment in the proposed technologies. However, the decision of whether to adopt these technologies was influenced not only by existing evidence on the proposed technologies and associated cost but other factors such as local disease burdens, hospital staff requirements (training, expertise), space requirements for the new MedTech, and its impact on organizing healthcare services and hospital workflows. Complementary technologies associated with radiation monitoring image visualization and control were identified.

Conclusions

Strategic MedTech investment requires a holistic approach that assigns equal weight to information arising by expert elicitation and hospital audit data with existing literature evidence. The decision for adoption is heavily influenced by the clinical expertise and hospital workflows.
OP127 Sugar And Spice And All Things NICE - Managed Access Agreements
Authors: Hall Adam , Liu Lok Wan , Macaulay Richard , Walsh Sean
Published: December 2019

Introduction

The National Institute for Health and Care Excellence (NICE) has increasingly agreed to reimburse innovative products with high levels of uncertainty as part of managed access agreements (MAAs) while additional data are collected, through the new Cancer Drugs Fund (CDF) or highly specialized technology (HST) pathways. This research aimed to review the data collection stipulations of current MAAs.

Methods

We reviewed all current MAAs entered into between NHS England and manufacturers as of 29 October 2018 and key data were extracted.

Results

Twenty-two MAAs were identified (19 through the CDF; three through HST). All MAAs involved an observational data collection component. The source of observational data collection was existing NHS databases (19/22 MAAs: 86.5 percent), existing independent registries (one MAA: 4.5 percent [ataluren]); bespoke MAA registry maintained by manufacturer (1/22 MAA: 4.5 percent [asfotase alfa]), and registries developed as a part of regulatory approval and maintained by the manufacturer (1/22 MAA: 4.5 percent [elosulfase alfa]). Only eight MAAs (asfotase alfa, ataluren, elosulfase alfa, brentuximab vedotin, venetoclax, ibrutinib, daratumumab, and pembrolizumab) had observational data collection as the primary method of data collection. Additionally, 17/22 MAAs (77 percent; all from the CDF) also required ongoing data collection from clinical trials as a key component of the data collection arrangement.

Conclusions

This research identified observational data collection as a requirement in all MAAs, which is primarily through existing registries (except ataluren, which required development of a bespoke registry), while ongoing trial data collection was limited to the CDF. The relatively low cost of using existing registries to fulfil data requirements, with the ability to achieve reimbursement whilst still collecting data from ongoing RCTs, make MAAs an attractive proposition for manufacturers. NICE reportedly plan to increase use of MAAs, with ongoing NICE consultation for changes in the appraisal process potentially allowing expansion to include all indications, which would mean increased opportunities to explore innovative MAAs to support access in the future.
OP135 CAR T-cell Therapy HTA Informs Australian Policy
Authors: Fennessy Paul , Clements Vanessa
Published: December 2019

Introduction

Chimeric antigen receptor (CAR) T-cell therapy is offered as a once-only treatment for patients with certain cancers that are not responsive to standard treatment. While clinicians, patients and their families increasingly seek access to CAR T-cell therapy, there is no revenue stream to support access through public or private health systems.

Methods

The New South Wales (NSW) Ministry of Health and Victorian Department of Health and Human Services oversighted a health technology assessment (HTA) to explore the status and geography of regulatory frameworks supporting delivery of CAR T-cell therapy, evidence for the safety, efficacy and cost, clinical trials conducted or underway and manufacturing aspects.

Results

CAR T-cell therapies are approved in the European Union and United States of America, and being considered in Australia, Canada, China and Japan. Efficacy, safety and cost-effectiveness is limited by the size and single-arm design of early stage trials and variation between them. While overall response ranges from 36–93 percent, early results for some cancers are less favorable. Durability of treatment effect is unknown, adverse events are common and can be life-threatening and risk of delayed onset toxicity remains unknown. Treatment requires access to approved manufacturing facilities (none in Australia) and specialist clinical staff.

Conclusions

CAR T-cell therapy is promising and demand is increasing, but the limited safety profile and evidence base should mitigate policy and investment decisions. Broader consideration should be given to developing, or identifying access to, manufacturing and clinical workforce capability and capacity to meet national demand. Australia is likely to encounter similar issues in other jurisdictions, such as limited evidence base and complex safety issues. Factors to be considered on a local and national basis for assessment and implementation include: (i) Regulatory support for industry; (ii) Strategies to manage uncertainties in long-term risks, benefits and costs; (iii) Access to accredited manufacturing facilities; (iv) Developing clinical and manufacturing workforce capability and capacity.
PP94 Clinical Effectiveness Of Regorafenib For Metastatic Colorectal Cancer
Authors: Absattarova Karlygash , Almadiyeva Alima , Sultanov Marat , Almatova Venera
Published: December 2019

Introduction

Colorectal cancer (CRC) is the third most common malignant neoplasm among men and the second most common among women. According to the World Cancer Report, the number of people suffering from this disease is growing steadily. In 2012, there were more than 1.36 million new cases of CRC, and approximately 694,000 people died from this disease worldwide.

Methods

A sensitive literature search identified 12 relevant publications, including: a CORRECT phase III study assessing the effect of regorafenib in patients with metastatic CRC that continued to progress despite using all standard treatment methods; a CONCUR Phase III study evaluating the clinical effect of regorafenib in Asian patients with metastatic CRC; a CONSIGN study conducted after the CORRECT and CONCUR studies that assessed the safety profile of regorafenib prior to market entry; and various systematic reviews evaluating the safety of regorafenib.

Results

The efficacy and safety of regorafenib for treating patients with metastatic CRC was evaluated in two major clinical studies: CORRECT and CONCUR. Although the studies were randomized, double-blind, and placebo-controlled, they were conducted in different patient populations. Before treatment with regorafenib, patients received, depending on the country, fluoropyrimidines, oxaliplatin, irinotecan, or bevacizumab, and patients with the wild-type KRAS gene also received cetuximab and panitumumab. Results from both studies indicated that regorafenib had a clinically significant positive effect on rates of progression-free survival and overall survival in patients with treatment-resistant metastatic CRC.

Conclusions

Regorafenib can be recommended as a monotherapy for resistant metastatic CRC when there are no contraindications to use. Considering the safety profile of regorafenib, further research is needed to determine the best dosage of regorafenib and the most appropriate clinical and molecular biomarkers for determining which patients would benefit most from this treatment.
PP139 Adapting Health Technology Assessment And Procurement To Tackle Antimicrobial Resistance
Authors: Neri Margherita , Towse Adrian , Hampson Grace , Henshall Christopher
Published: December 2019

Introduction

The rise of antimicrobial resistance (AMR) as an international public health threat calls urgently for improved stewardship of antibiotics and for the development of new antibiotics to tackle AMR. There is growing agreement that changes are needed to existing systems for health technology assessment (HTA) and procurement if antibiotics are to be used appropriately, and manufacturers are to receive rewards that incentivize research and development. However, there has been little discussion of what changes might actually be made.

Methods

We conducted a literature review of recent proposals to modify HTA and contracting for antibiotics, and interviewed HTA experts from England, France, Germany, Italy, Japan, and Sweden to explore the attractiveness of these and other proposals in their countries. A forum (held in February 2019) with government and health system representatives from these countries, as well as from industry, will promote face-to-face discussions on practical ways to modify approaches in these countries to recognize the full value of antibiotics and promote responsible stewardship.

Results

The focus of the main proposal is to define value attributes that reflect the societal impact of antibiotics, model the dynamics of infection transmission and resistance development, and conceptualize payment models that delink volumes sold from final revenues. However, HTA experts perceived a number of issues with these proposals, including a lack of data to demonstrate societal value, complex modeling techniques that require advanced capabilities, uncertain value estimates, and lack of alignment with current approaches. At present, it appears that only England and Sweden have started to actively address HTA and contracting for antibiotics as a priority.

Conclusions

Preliminary findings suggested that efforts and progress on modifying HTA and contracting of antibiotics have been heterogeneous so far. The forum will shed further light on possible ways forward within the two value assessment approaches of clinical added benefit and quality-adjusted life years.
PP151 Establishing Health Technology Assessment Impact Evaluation With Stakeholder Input From Day One
Authors: Poole Ruth Louise , Hughes Sophie , Elston Lauren , Myles Susan
Published: December 2019

Introduction

Health Technology Wales (HTW) is a relatively new Health Technology Assessment (HTA) agency which focuses on non-medicines. In common with other HTA organizations, it identifies and appraises a range of technologies. However, HTW is also looking beyond the publication of guidance, to assess the adoption of advice and its eventual impact.

Methods

HTW commissioned development of an Evaluation Plan from independent experts (Matter of Focus). A literature review was carried out to inform an options appraisal of methods for assessing impact. The selected approach was Contribution Analysis, which estimates the counterfactual through engagement of stakeholders.

Results

Whilst it is too early to report the full impact of HTW's guidance, a number of activities have taken place to prepare for evaluation. The core HTW team developed a series of logic models to describe the anticipated impact, the mechanisms by which it would be achieved, and key assumptions. Stakeholders were consulted for insight from a range of perspectives, and to manage expectations. This was achieved through individual interviews, presentation and discussion at committee meetings, and the sharing of written materials for feedback. This information was collated to populate bespoke software (OutNav). The collection of data relating to processes, outputs and outcomes is already an ongoing routine task of researchers and support staff.

Conclusions

HTW has an opportunity to build impact evaluation into its culture from the beginning. This will facilitate the future reporting of HTW's influence using a well-designed, evidence-based approach. Furthermore, this pioneering work will clearly demonstrate the value of HTA to funders, commissioners, governments, and other decision-making bodies.
PP189 Filling In The Blanks: Is RWE From MAAs Used In NICE Decision Making?
Authors: Liu Lok Wan , Hall Adam , Macaulay Richard , Walsh Sean
Published: December 2019

Introduction

The National Institute for Health and Care Excellence (NICE) may recommend temporary funding through managed access agreements (MAAs) for oncology drugs (via the Cancer Drugs Fund [CDF]) and highly specialized therapies for rare diseases. MAAs allow for the collection of evidence to address key areas of clinical uncertainty, while providing access of medicines to patients, prior to re-appraisal by NICE. Observational data and other real-world evidence (RWE) are crucial requirements for all MAAs and herein we examine the extent these data are being used to inform HTA decisions at re-appraisal.

Methods

Existing MAAs entered into between the National Health Service (NHS) England and manufacturers as of 30 October 2018 were identified; for drug:indication pairings with NICE re-appraisals, all information was reviewed and the key data extracted.

Results

Of the twenty-two MAAs identified, only two drug:indication pairings have been subsequently re-appraised by NICE: BV(brentuximab vedotin):non-Hodgkin lymphoma (’recommended’) and pembrolizumab:relapsed or refractory classical Hodgkin lymphoma (’recommended’). Data from a retrospective questionnaire regarding the proportion of patients that received curative stem cell transplant (SCT) post-BV (from patients who received BV in the old CDF) were accepted to provide sufficient evidence on the post-BV SCT rate by NICE. Meanwhile, for pembrolizumab, long-term survival benefit was the key clinical uncertainty; the primary data collection source was updated phase III randomized controlled trial data. At re-appraisal no reference was made to the observational data component; more mature survival data reduced uncertainty over survival benefits and were sufficient to support a positive NICE recommendation.

Conclusions

Of the twenty-two MAAs to date, only two drugs have been re-appraised thus far, with both receiving positive NICE recommendations. Observational data were successfully used to address key clinical uncertainties regarding subsequent real-world treatment patterns for BV, but observational data were not referred to in the NICE recommendation for pembrolizumab. The re-appraisal of more drugs in the future will clarify the importance being placed on observational data collection requested by NICE for existing MAAs.
VP33 Pharmacoeconomic Submission Requirements: Africa Compared With England
Authors: Marsh Sophia , Truter Ilse
Published: December 2019

Introduction

The South African Pharmacoeconomic Submissions Guideline (SAPG) is currently voluntary for medicines in the private health sector but may become mandatory and more widely used under the proposed National Health Insurance system. To make recommendations on evidence generation and areas where the SAPG could be strengthened, the study compared the SAPG requirements with other African pharmacoeconomic guidelines and the National Institute for Health and Care Excellence Methods Guide (NICE MG).

Methods

The World Health Organisation, International Network of Agencies for Health Technology Assessment (INAHTA), HTA International, and the International Society for Pharmacoeconomics and Outcomes Research websites were consulted, and email requests sent to named individuals from retrieved source material. The European Network for HTA Core Model® (version 3.0) (the Model®) provided the evaluation and comparison framework, using three criteria: completely, partly or not completely requiring the same or similar information as the Model®.

Results

Of the forty-five countries identified, only Egypt had a publicly available pharmacoeconomic guideline (Egyptian Pharmacoeconomic Guideline (EPG)). The guidelines varied considerably in their intended audience, size and content. All three guidelines’ primary focus was the cost and economic evaluation, and health problem and current use domains. Safety, organisational, ethical and legal aspects were poorly covered by the SAPG and EPG guidelines (less than thirty percent of issues in each domain completely / partly covered). The SAPG completely or partly required the same or similar information in the Model® for thirty-nine percent of total issues, the EPG thirty-three percent and the NICE MG sixty-six percent

Conclusions

The SAPG was not as comprehensive as the NICE MG and poorly covered some key aspects of HTAs, suggesting that the SAPG could be developed to be more informative for decision-makers. Evidence generation should focus on describing the health problem the technology is targeting and on evidence that can be synthesized into cost-effectiveness analyses.
High mass X-ray binaries as progenitors of gravitational wave sources
Authors: Klencki Jakub , Nelemans Gijs
Published: December 2019

X-ray binaries with black hole (BH) accretors and massive star donors at short orbital periods of a few days can evolve into close binary BH (BBH) systems that merge within the Hubble time. From an observational point of view, upon the Roche-lobe overflow such systems will most likely appear as ultra-luminous X-ray sources (ULXs). To study this connection, we compute the mass transfer phase in systems with BH accretors and massive star donors (M > 15 Mʘ) at various orbital separations and metallicities. In the case of core-hydrogen and core-helium burning donors (cases A and C of mass transfer) we find the typical duration of super-Eddington mass transfer of up to 106 and 105 yr, with rates of 10−6 and 10−5Mʘ yr-1, respectively. Given that roughly 0.5 ULXs are found per unit of star formation rate, we estimate the rate of BBH mergers from stable mass transfer evolution to be at most 10 Gpc−3 yr−1.
Formation of the SMC WO+O binary AB8
Authors: Wang Chen , Langer Norbert , Gräfener Götz , Marchant Pablo
Published: December 2019

Wolf-Rayet (WR) stars are stripped stellar cores that form through strong stellar wind or binary mass transfer. It is proposed that binary evolution plays a vital role in the formation of WR stars in low metallicity environments due to the metallicity dependance of stellar winds. However observations indicate a similar binary fraction of WR stars in the Small Magellanic Cloud (SMC) compared to the Milky Way. There are twelve WR stars in the SMC and five of them are members of binary systems. One of them (SMC AB8) harbors a WO type star. In this work we explore possible formation channels of this binary. We use the MESA code to compute large grids of binary evolution models, and then use least square fitting to compare our models with the observations. In order to reproduce the key properties of SMC AB8, we require efficient semiconvection to produce a sufficiently large convective core, as well as a longer He-burning lifetime. We also need a high mass loss rate during the WN stage to assist the removal of the outer envelope. In this way, we can reproduce the observed properties of AB8, except for the surface carbon to oxygen ratio, which requires further investigation.
On the origin of Supergiant Fast X-ray Transients
Authors: Hubrig Swetlana , Sidoli Lara , Postnov Konstantin A. , Schöller Markus , Kholtygin Alexander F. , Järvinen Silva P.
Published: December 2019

. A fraction of high-mass X-ray binaries are supergiant fast X-ray transients. These systems have on average low X-ray luminosities, but display short flares during which their X-ray luminosity rises by a few orders of magnitude. The leading model for the physics governing this X-ray behaviour suggests that the winds of the donor OB supergiants are magnetized. In agreement with this model, the first spectropolarimetric observations of the SFXT IGR J11215-5952 using the FORS 2 instrument at the Very Large Telescope indicate the presence of a kG longitudinal magnetic field. Based on these results, it seems possible that the key difference between supergiant fast X-ray transients and other high-mass X-ray binaries are the properties of the supergiant’s stellar wind and the physics of the wind’s interaction with the neutron star magnetosphere.
Analytical solution for magnetized thin accretion disk in comparison with numerical simulations
Authors: Čemeljić Miljenko , Parthasarathy Varadarajan , Kluźniak Włodek
Published: December 2019

We obtained equations for a thin magnetic accretion disk, using the method of asymptotic approximation. They cannot be solved analytically-without solutions for a magnetic field in the magnetosphere between the star and the disk, only a set of general conditions on the solutions can be derived. To compare the analytical results with numerical solutions, we find expressions for physical quantities in the disk, using our results from resistive and viscous star-disk magnetospheric interaction simulations.
Optical interferometry of High-Mass X-ray Binaries: Resolving wind, disk and jet outflows at sub-milliarcsecond scale
Authors: Waisberg Idel , Dexter Jason , Petrucci P.-O. , Dubus Guillaume , Perraut Karine ,   GRAVITY Collaboration
Published: December 2019

Because of their small angular size < 1 mas, spatial information on High-mass X-ray binaries (HMXB) has typically been inferred from photometry or spectroscopy. Optical interferometry offers the possibility to spatially resolve such systems, but has been traditionally limited to bright targets or low spectral resolution. The VLTI instrument GRAVITY, working in the near-infrared K band, achieves unprecedented precision in differential interferometric quantities at high spectral resolution, allowing to study HMXBs through the lens of optical interferometry for the first time. We present GRAVITY observations on two X-ray binaries: the microquasar SS 433 and the supergiant HMXB BP Cru. The former is the only known steady super-Eddington accretor in the Galaxy and is in a unique stage of binary evolution, with probable ties to at least part of the ULX population. With GRAVITY, we resolve its massive winds and optical baryonic jets for the first time, finding evidence for powerful equatorial outflows and photoionization as the main heating process along the jets. BP Cru harbors an X-ray pulsar accreting from the wind of its early-blue hypergiant companion Wray 977. The GRAVITY observations resolve the inner parts of the stellar wind and allow probing the influence of the orbiting pulsar on the circumstellar environment.
The dark side of supergiant High-Mass X-ray Binaries
Authors: Chaty Sylvain , Fortin Francis , García Federico , Fogantini Federico
Published: December 2019

. High Mass X-ray Binaries (HMXB) have been revealed by a wealth of multi-wavelength observations, from X-ray to optical and infrared domain. After describing the 3 different kinds of HMXB, we focus on 3 HMXB hosting supergiant stars: IGR J16320-4751, IGR J16465-4507 and IGR J16318-4848, respectively called “The Good”, “The Bad” and “The Ugly”. We review in these proceedings what the observations of these sources have brought to light concerning our knowledge of HMXB, and what part still remains in the dark side. Many questions are still pending, related to accretion processes, stellar wind properties in these massive and active stars, and the overall evolution due to transfer of mass and angular momentum between the companion star and the compact object. Future observations should be able to answer these questions, which constitute the dark side of HMXB.
High-Mass X-ray Binaries: progenitors of double compact objects
Authors: van den Heuvel Edward P. J.
Published: December 2019

A summary is given of the present state of our knowledge of High-Mass X-ray Binaries (HMXBs), their formation and expected future evolution. Among the HMXB-systems that contain neutron stars, only those that have orbital periods upwards of one year will survive the Common-Envelope (CE) evolution that follows the HMXB phase. These systems may produce close double neutron stars with eccentric orbits. The HMXBs that contain black holes do not necessarily evolve into a CE phase. Systems with relatively short orbital periods will evolve by stable Roche-lobe overflow to short-period Wolf-Rayet (WR) X-ray binaries containing a black hole. Two other ways for the formation of WR X-ray binaries with black holes are identified: CE-evolution of wide HMXBs and homogeneous evolution of very close systems. In all three cases, the final product of the WR X-ray binary will be a double black hole or a black hole neutron star binary.
Different generations of HMXBs: clues about their formation efficiency from Magellanic Clouds studies
Authors: Antoniou Vallia , Zezas Andreas , Drake Jeremy J. , Badenes Carles , Haberl Frank , Hong Jaesub , Plucinsky Paul P. ,   the SMC XVP Collaboration Team
Published: December 2019

Nearby star-forming galaxies offer a unique environment to study the populations of young (<100 Myr) accreting binaries. These systems are tracers of past populations of massive stars that heavily affect their immediate environment and parent galaxies. Using a Chandra X-ray Visionary program, we investigate the young neutron-star binary population in the low metallicity of the Small Magellanic Cloud (SMC) by reaching quiescent X-ray luminosity levels (~few times 1032 erg/s). We present the first measurement of the formation efficiency of high-mass X-ray binaries (HMXBs) as a function of the age of their parent stellar populations by using 3 indicators: the number ratio of HMXBs to OB stars, to the SFR, and to the stellar mass produced during the specific star-formation burst they are associated with. In all cases, we find that the HMXB formation efficiency increases as a function of time up to ~40–60 Myr, and then gradually decreases.
On the nature of the 35-day cycle in the X-ray binary Her X-1/HZ Her
Authors: Shakura N. , Kolesnikov D. , Postnov K. , Volkov I. , Bikmaev I. , Irsmambetova T. , Staubert R. , Wilms J. , Irtuganov E. , Shurygin P. , Golysheva P. , Shugarov S. , Nikolenko I. , Trunkovsky E. , Schonherr G. , Schwope A. , Klochkov D.
Published: December 2019

The X-ray binary Her X-1 consists of an accreting neutron star and the optical companion HZ Her. The 35-day X-ray variability of this system is known since its discovery in 1972 by the UHURU satellite and is believed to be caused by forced precession of the warped accretion disk tilted to the orbital plane. We argue that the observed features of the optical variability of HZ Her can be explained by free precession of the neutron star with a period close to that of the forced disk precession. The model parameters include a) the intensity (power) of the stream of matter flowing out of the optical star; b) the X-ray luminosity of the neutron star; c) the optical flux of the accretion disk; d) the X-ray irradiation pattern on the donor star; e) the tilt of the inner and outer edge of the accretion disk. A possible synchronization mechanism based on the coupling between the neutron star free precession and the dynamical action of non-stationary gas streams is discussed shortly.
The young Be-star binary Circinus X-1
Authors: Schulz Norbert S. , Kallman Timothy E. , Heinz Sebastian , Sell Paul , Jonker Peter , Brandt William N.
Published: December 2019

Cir X-1 is a young X-ray binary exhibiting X-ray flux changes of four orders of magnitude over several decades. It has been observed many times since the launch of the Chandra X-ray Observatory with high energy transmission grating spectrometer and each time the source gave us a vastly different look. At its very lowest X-ray flux we found a single 1.7 keV blackbody spectrum with an emission radius of 0.5 km. Since the neutron star in Cir X-1 is only few thousand years old we identify this as emission from an accretion column since at this youth the neutron star is assumed to be highly magnetized. At an X-ray flux of 1.8×10−11 erg cm−2 s−1 this implies a moderate magnetic field of a few times of 1011 G. The photoionized X-ray emission line properties at this low flux are consistent with B5-type companion wind. We suggest that Cir X-1 is a very young Be-star binary.
Evolution of the Global Carbon Cycle and Climate Regulation on Earth
Authors: Isson T. T. , Planavsky N. J. , Coogan L. A. , Stewart E. M. , Ague J. J. , Bolton E. W. , Zhang S. , McKenzie N. R. , Kump L. R.
Published: December 2019

The existence of stabilizing feedbacks within Earth's climate system is generally thought to be necessary for the persistence of liquid water and life. Over the course of Earth's history, Earth's atmospheric composition appears to have adjusted to the gradual increase in solar luminosity, resulting in persistently habitable surface temperatures. With limited exceptions, the Earth system has been observed to recover rapidly from pulsed climatic perturbations. Carbon dioxide (CO2) regulation via negative feedbacks within the coupled global carbon‐silica cycles are classically viewed as the main processes giving rise to climate stability on Earth. Here we review the long‐term global carbon cycle budget, and how the processes modulating Earth's climate system have evolved over time. Specifically, we focus on the relative roles that shifts in carbon sources and sinks have played in driving long‐term changes in atmospheric pCO2. We make the case that marine processes are an important component of the canonical silicate weathering feedback, and have played a much more important role in pCO2 regulation than traditionally imagined. Notably, geochemical evidence indicate that the weathering of marine sediments and off‐axis basalt alteration act as major carbon sinks. However, this sink was potentially dampened during Earth's early history when oceans had higher levels of dissolved silicon (Si), iron (Fe), and magnesium (Mg), and instead likely fostered more extensive carbon recycling within the ocean‐atmosphere system via reverse weathering—that in turn acted to elevate ocean‐atmosphere CO2 levels.
Effect of Fluid Viscosity on Fault Reactivation and Coseismic Weakening
Authors: Cornelio C. , Passelègue F. X. , Spagnuolo E. , Di Toro G. , Violay M.
Published: December 2019

High‐viscosity fluids are often used during hydraulic fracking operations in georeservoirs. Here we performed dedicated experiments to study the influence of fluid viscosity on fault reactivation and associated induced earthquakes. Experiments were conducted in the rotary‐shear machine Slow to HIgh Velocity Apparatus on experimental fault of Westerly granite saturated by fluids with increasing viscosity (at room temperature) from 0.1 mPa s (water) to 1.2 Pa s (99% glycerol). Fault reactivation was triggered at constant effective normal stress by increasing the shear stress acting on the fault. Our results showed that independent of the viscosity, fault reactivation followed a Coulomb‐failure criterion. Instead, fluid viscosity affected the fault weakening mechanism: flash heating was the dominant weakening mechanism in room humidity and water‐saturated conditions, whereas the presence of more viscous fluids favored the activation of elasto‐hydrodynamic lubrication. Independent of the weakening mechanism, the breakdown work Wb dissipated during seismic faulting increased with slip U following a power law (Wb ∝ U 1.25) in agreement with seismological estimates of natural and induced earthquakes.
A novel microscale selective laser sintering (μ-SLS) process for the fabrication of microelectronic parts
Authors: Roy Nilabh K. , Behera Dipankar , Dibua Obehi G. , Foong Chee S. , Cullinan Michael A.
Published: December 2019

One of the biggest challenges in microscale additive manufacturing is the production of three-dimensional, microscale metal parts with a high enough throughput to be relevant for commercial applications. This paper presents a new microscale additive manufacturing process called microscale selective laser sintering (μ-SLS) that can produce true 3D metal parts with sub-5 μm resolution and a throughput of greater than 60 mm3/hour. In μ-SLS, a layer of metal nanoparticle ink is first coated onto a substrate using a slot die coating system. The ink is then dried to produce a uniform nanoparticle layer. Next, the substrate is precisely positioned under an optical subsystem using a set of coarse and fine nanopositioning stages. In the optical subsystem, laser light that has been patterned using a digital micromirror array is used to heat and sinter the nanoparticles into the desired patterns. This set of steps is then repeated to build up each layer of the 3D part in the μ-SLS system. Overall, this new technology offers the potential to overcome many of the current limitations in microscale additive manufacturing of metals and become an important process in microelectronics packaging applications.
Layered material platform for surface plasmon resonance biosensing
Authors: Wu F. , Thomas P. A. , Kravets V. G. , Arola H. O. , Soikkeli M. , Iljin K. , Kim G. , Kim M. , Shin H. S. , Andreeva D. V. , Neumann C. , Küllmer M. , Turchanin A. , De Fazio D. , Balci O. , Babenko V. , Luo B. , Goykhman I. , Hofmann S. , Ferrari A. C. , Novoselov K. S. , Grigorenko A. N.
Published: December 2019

Plasmonic biosensing has emerged as the most sensitive label-free technique to detect various molecular species in solutions and has already proved crucial in drug discovery, food safety and studies of bio-reactions. This technique relies on surface plasmon resonances in ~50 nm metallic films and the possibility to functionalize the surface of the metal in order to achieve selectivity. At the same time, most metals corrode in bio-solutions, which reduces the quality factor and darkness of plasmonic resonances and thus the sensitivity. Furthermore, functionalization itself might have a detrimental effect on the quality of the surface, also reducing sensitivity. Here we demonstrate that the use of graphene and other layered materials for passivation and functionalization broadens the range of metals which can be used for plasmonic biosensing and increases the sensitivity by 3-4 orders of magnitude, as it guarantees stability of a metal in liquid and preserves the plasmonic resonances under biofunctionalization. We use this approach to detect low molecular weight HT-2 toxins (crucial for food safety), achieving phase sensitivity~0.5 fg/mL, three orders of magnitude higher than previously reported. This proves that layered materials provide a new platform for surface plasmon resonance biosensing, paving the way for compact biosensors for point of care testing.
Structured Back Focal Plane Interferometry (SBFPI)
Authors: Upadhya Avinash , Zheng Yujie , Li Li , Lee Woei Ming
Published: December 2019

Back focal plane interferometry (BFPI) is one of the most straightforward and powerful methods for achieving sub-nanometer particle tracking precision at high speed (MHz). BFPI faces technical challenges that prohibit tunable expansion of linear detection range with minimal loss to sensitivity, while maintaining robustness against optical aberrations. In this paper, we devise a tunable BFPI combining a structured beam (conical wavefront) and structured detection (annular quadrant photodiode). This technique, which we termed Structured Back Focal Plane Interferometry (SBFPI), possesses three key novelties namely: extended tracking range, low loss in sensitivity, and resilience to spatial aberrations. Most importantly, the conical wavefront beam preserves the axial Gouy phase shift and lateral beam waist that can then be harnessed in a conventional BFPI system. Through a series of experimental results, we were able to tune detection sensitivity and detection range over the SBFPI parameter space. We also identified a figure of merit based on the experimental optimum that allows us to identify optimal SBPFI configurations that balance both range and sensitivity. In addition, we also studied the resilience of SBFPI against asymmetric spatial aberrations (astigmatism of up to 0.8 λ) along the lateral directions. The simplicity and elegance of SBFPI will accelerate its dissemination to many associated fields in optical detection, interferometry and force spectroscopy.
The Levantine jellyfish Rhopilema nomadica and Rhizostoma pulmo swim faster against the flow than with the flow
Authors: Malul Dror , Lotan Tamar , Makovsky Yizhaq , Holzman Roi , Shavit Uri
Published: December 2019

Jellyfish locomotion and orientation have been studied in the past both in the laboratory, testing mostly small jellyfish, and in the field, where it was impossible to control the seawater currents. Utilizing an outdoor water flume, we tested the locomotion of jellyfish when swimming against and with currents of up to 4.5 cm s−1. We used adult jellyfish from two of the most abundant species in the eastern Mediterranean, Rhopilema nomadica and Rhizostoma pulmo, and measured their pulsation frequency and swimming speed relative to the water. While pulsation frequency was not affected by the water velocity, jellyfish swam faster against the current than with it. This finding suggests that jellyfish possess a sensory ability, whose mechanism is currently unknown, enabling them to gauge the flow and react to it, possibly in order to reduce the risk of stranding.
Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB/c mice reduce parasite load
Authors: da Fonseca-Martins Alessandra M. , Ramos Tadeu D. , Pratti Juliana E. S. , Firmino-Cruz Luan , Gomes Daniel Claudio Oliveira , Soong Lynn , Saraiva Elvira M. , de Matos Guedes Herbert L.
Published: December 2019

Leishmaniasis is a neglected disease, for which current treatment presents numerous issues.Leishmania amazonensisis the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. In this study, we observed thatL. amazonensisinduced PD-1 expression on both CD4+and CD8+T cells and PD-L1 on dendritic cells on BALB/c mice. We tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healingL. amazonensisinfection in BALB/c mice, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-γ-producing CD4+and CD8+T cells, respectively. Compared with infection controls, mice treated with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-Leishmaniaantibody (IgM, IgG, IgG1 and IgG2a) or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-β production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.
Short-term effects of air pollution on blood pressure
Authors: Choi You-Jung , Kim Sun-Hwa , Kang Si-Hyuck , Kim Sun-Young , Kim Ok-Jin , Yoon Chang-Hwan , Lee Hae-Young , Youn Tae-Jin , Chae In-Ho , Kim Cheol-Ho
Published: December 2019

Elevated blood pressure (BP) has been proposed as a possible pathophysiological mechanism linking exposure to ambient air pollution and the increased risk of cardiovascular mortality and morbidity. In this study, we investigated the hourly relationship between ambient air pollutants and BP. BP measurements were extracted from the electronic health record database of the Seoul National University Bundang Hospital from February 2015 to June 2017. A total of 98,577 individual BP measurements were matched to the hourly levels of air pollutants. A generalized additive model was constructed for hour lags of 0–8 of air pollutants adjusting for age, sex, meteorological variables, and time trend. Systolic BP was shown to be significantly lower at 2–4 hours and 3–5 hours after increased levels of SO2 and CO, respectively (0.24 mmHg and 0.26 mmHg for an interquartile range, respectively). In contrast, O3 and NO2 were associated with significantly increased systolic BP at 3–5 lag hours and at 0–2 lag hours, respectively. BP elevation in association with O3 and NO2 was shown to be significantly greater in hypertensive patients than normotensive subjects. Our findings suggest that short-term exposure to air pollution may be associated with elevated BP.
RORγt+ Treg to Th17 ratios correlate with susceptibility to Giardia infection
Authors: Yordanova Ivet A. , Cortés Alba , Klotz Christian , Kühl Anja A. , Heimesaat Markus M. , Cantacessi Cinzia , Hartmann Susanne , Rausch Sebastian
Published: December 2019

Infections withGiardiaare among the most common causes of food and water-borne diarrheal disease worldwide. Here, we investigated Th17, Treg and IgA responses, and alterations in gut microbiota in two mouse lines with varying susceptibility toGiardia murisinfection. Infected BALB/c mice shed significantly more cysts compared with C57BL/6 mice. Impaired control of infection in BALB/c mice was associated with lower Th17 activity and lower IgA levels compared with C57BL/6 mice. The limited metabolic activity, proliferation and cytokine production of Th17 cells in BALB/c mice was associated with higher proportions of intestinal Foxp3+RORγt+regulatory T cells and BALB/c mice developed increased RORγt+Treg:Th17 ratios in response toG. murisinfection. Furthermore,G. muriscolonization led to a significantly reduced evenness in the gut microbial communities of BALB/c mice. Our data indicate that differential susceptibility toGiardiainfections may be related to RORγt+Treg controlling Th17 activity and that changes in the microbiota composition uponGiardiainfection partially depend on the host background.