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Κυριακή 9 Ιουλίου 2017

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Implementing the Synchronized Global Switch from Trivalent to Bivalent Oral Polio Vaccines—Lessons Learned From the Global Perspective

Abstract
In 2015, the Global Commission for the Certification of Polio Eradication certified the eradication of type 2 wild poliovirus, 1 of 3 wild poliovirus serotypes causing paralytic polio since the beginning of recorded history. This milestone was one of the key criteria prompting the Global Polio Eradication Initiative to begin withdrawal of oral polio vaccines (OPV), beginning with the type 2 component (OPV2), through a globally synchronized initiative in April and May 2016 that called for all OPV using countries and territories to simultaneously switch from use of trivalent OPV (tOPV; containing types 1, 2, and 3 poliovirus) to bivalent OPV (bOPV; containing types 1 and 3 poliovirus), thus withdrawing OPV2. Before the switch, immunization programs globally had been using approximately 2 billion tOPV doses per year to immunize hundreds of millions of children. Thus, the globally synchronized withdrawal of tOPV was an unprecedented achievement in immunization and was part of a crucial strategy for containment of polioviruses. Successful implementation of the switch called for intense global coordination during 2015–2016 on an unprecedented scale among global public health technical agencies and donors, vaccine manufacturers, regulatory agencies, World Health Organization (WHO) and United Nations Children's Fund (UNICEF) regional offices, and national governments. Priority activities included cessation of tOPV production and shipment, national inventories of tOPV, detailed forecasting of tOPV needs, bOPV licensing, scaling up of bOPV production and procurement, developing national operational switch plans, securing funding, establishing oversight and implementation committees and teams, training logisticians and health workers, fostering advocacy and communications, establishing monitoring and validation structures, and implementing waste management strategies. The WHO received confirmation that, by mid May 2016, all 155 countries and territories that had used OPV in 2015 had successfully withdrawn OPV2 by ceasing use of tOPV in their national immunization programs. This article provides an overview of the global efforts and challenges in successfully implementing this unprecedented global initiative, including (1) coordination and tracking of key global planning milestones, (2) guidance facilitating development of country specific plans, (3) challenges for planning and implementing the switch at the global level, and (4) best practices and lessons learned in meeting aggressive switch timelines. Lessons from this monumental public health achievement by countries and partners will likely be drawn upon when bOPV is withdrawn after polio eradication but also could be relevant for other global health initiatives with similarly complex mandates and accelerated timelines.

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Transition Planning For After Polio Eradication

Abstract
The Global Polio Eradication Initiative (GPEI) has been in operation since 1988, now spends $1 billion annually, and operates through thousands of staff and millions of volunteers in dozens of countries. It has brought polio to the brink of eradication. After eradication is achieved, what should happen to the substantial assets, capabilities, and lessons of the GPEI? To answer this question, an extensive process of transition planning is underway. There is an absolute need to maintain and mainstream some of the functions, to keep the world polio-free. There is also considerable risk—and, if seized, substantial opportunity—for other health programs and priorities. And critical lessons have been learned that can be used to address other health priorities. Planning has started in the 16 countries where GPEI's footprint is the greatest and in the program's 5 core agencies. Even though poliovirus transmission has not yet been stopped globally, this planning process is gaining momentum, and some plans are taking early shape. This is a complex area of work—with difficult technical, financial, and political elements. There is no significant precedent. There is forward motion and a willingness on many sides to understand and address the risks and to explore the opportunities. Very substantial investments have been made, over 30 years, to eradicate a human pathogen from the world for the second time ever. Transition planning represents a serious intent to responsibly bring the world's largest global health effort to a close and to protect and build upon the investment in this effort, where appropriate, to benefit other national and global priorities. Further detailed technical work is now needed, supported by broad and engaged debate, for this undertaking to achieve its full potential.

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Addressing the Challenges and Opportunities of the Polio Endgame: Lessons for the Future

Abstract
The Global Commission for the Certification of the Eradication of Poliomyelitis certified the eradication of type 2 poliovirus in September 2015, making type 2 poliovirus the first human pathogen to be eradicated since smallpox. The eradication of type 2 poliovirus, the absence of detection of type 3 poliovirus worldwide since November 2012, and cornering type 1 poliovirus to only a few geographic areas of 3 countries has enabled implementation of the endgame of polio eradication which calls for a phased withdrawal of oral polio vaccine beginning with the type 2 component, introduction of inactivated poliovirus vaccine, strengthening of routine immunization in countries with extensive polio resources, and initiating activities to transition polio resources, program experience, and lessons learned to other global health initiatives. This supplement focuses on efforts by global partners to successfully launch polio endgame activities to permanently secure and sustain the enormous gains of polio eradication forever.

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Lessons Learned and Legacy of the Stop Transmission of Polio Program

Abstract
In 1988, the by the World Health Assembly established the Global Polio Eradication Initiative, which consisted of a partnership among the World Health Organization (WHO), Rotary International, the Centers for Disease Control and Prevention (CDC), and the United Nations Children's Fund. By 2016, the annual incidence of polio had decreased by >99.9%, compared with 1988, and at the time of writing, only 3 countries in which wild poliovirus circulation has never been interrupted remain: Afghanistan, Nigeria, and Pakistan. A key strategy for polio eradication has been the development of a skilled and deployable workforce to implement eradication activities across the globe. In 1999, the Stop Transmission of Polio (STOP) program was developed and initiated by the CDC, in collaboration with the WHO, to train and mobilize additional human resources to provide technical assistance to polio-endemic countries. STOP has also informed the development of other public health workforce capacity to support polio eradication efforts, including national STOP programs. In addition, the program has diversified to address measles and rubella elimination, data management and quality, and strengthening routine immunization programs. This article describes the STOP program and how it has contributed to polio eradication by building global public health workforce capacity.

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Cold-Chain Adaptability During Introduction of Inactivated Polio Vaccine in Bangladesh, 2015

Abstract
Background.
Introduction of inactivated polio vaccine creates challenges in maintaining the cold chain for vaccine storage and distribution.
Methods.
We evaluated the cold chain in 23 health facilities and 36 outreach vaccination sessions in 8 districts and cities of Bangladesh, using purposive sampling during August–October 2015. We interviewed immunization and cold-chain staff, assessed equipment, and recorded temperatures during vaccine storage and transportation.
Results.
All health facilities had functioning refrigerators, and 96% had freezers. Temperature monitors were observed in all refrigerators and freezers but in only 14 of 66 vaccine transporters (21%). Recorders detected temperatures >8°C for >60 minutes in 5 of 23 refrigerators (22%), 3 of 6 cold boxes (50%) transporting vaccines from national to subnational depots, and 8 of 48 vaccine carriers (17%) used in outreach vaccination sites. Temperatures <2°C were detected in 4 of 19 cold boxes (21%) transporting vaccine from subnational depots to health facilities and 14 of 48 vaccine carriers (29%).
Conclusions.
Bangladesh has substantial cold-chain storage and transportation capacity after inactivated polio vaccine introduction, but temperature fluctuations during vaccine transport could cause vaccine potency loss that could go undetected. Bangladesh and other countries should strive to ensure consistent and sufficient cold-chain storage and monitor the cold chain during vaccine transportation at all levels.

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The Switch From Trivalent to Bivalent Oral Poliovirus Vaccine in the South-East Asia Region

Abstract
This analysis describes an innovative and successful approach to risk identification and mitigation in relation to the switch from trivalent to bivalent oral polio vaccine (OPV) in the 11 countries of the World Health Organization's (WHO's) South-East Asia Region (SEAR) in April 2016.The strong commitment of governments and immunization professionals to polio eradication and an exemplary partnership between the WHO, United Nations Children's Fund (UNICEF), and other partners and stakeholders in the region and globally were significant contributors to the success of the OPV switch in the SEAR. Robust national switch plans were developed and country-specific innovations were planned and implemented by the country teams. Close monitoring and tracking of the activities and milestones through dashboards and review meetings were undertaken at the regional level to ensure that implementation time lines were met, barriers identified, and solutions for overcoming challenges were discussed and implemented.The SEAR was the first WHO Region globally to complete the switch and declare the successful withdrawal of trivalent OPV from all countries on 17 May 2016.A number of activities implemented during the switch process are likely to contribute positively to existing immunization practices and to similar initiatives in the future. These activities include better vaccine supply chain management, improved mechanisms for disposal of vaccination-related waste materials, and a closer collaboration with drug regulators, vaccine manufacturers, and the private sector for immunization-related initiatives.

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Assessing Inactivated Polio Vaccine Introduction and Utilization in Kano State, Nigeria, April–November 2015

Abstract
Background.
Kano State, Nigeria, introduced inactivated polio vaccine (IPV) into its routine immunization (RI) schedule in March 2015 and was the pilot site for an RI data module for the National Health Management Information System (NHMIS). We determined factors impacting IPV introduction and the value of the RI module on monitoring new vaccine introduction.
Methods.
Two assessment approaches were used: (1) analysis of IPV vaccinations reported in NHMIS, and (2) survey of 20 local government areas (LGAs) and 60 associated health facilities (HF).
Results.
By April 2015, 66% of LGAs had at least 20% of HFs administering IPV, by June all LGAs had HFs administering IPV and by July, 91% of the HFs in Kano reported administering IPV. Among surveyed staff, most rated training and implementation as successful. Among HFs, 97% had updated RI reporting tools, although only 50% had updated microplans. Challenges among HFs included: IPV shortages (20%), hesitancy to administer 2 injectable vaccines (28%), lack of knowledge on multi-dose vial policy (30%) and age of IPV administration (8%).
Conclusion.
The introduction of IPV was largely successful in Kano and the RI module was effective in monitoring progress, although certain gaps were noted, which should be used to inform plans for future vaccine introductions.

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Lessons Learned From Managing the Planning and Implementation of Inactivated Polio Vaccine Introduction in Support of the Polio Endgame

Abstract
The Immunization Systems Management Group (IMG) was established as a time-limited entity, responsible for the management and coordination of Objective 2 of the Polio Eradication and Endgame Strategic Plan. This objective called for the introduction of at least 1 dose of inactivated polio vaccine (IPV) into the routine immunization programs of all countries using oral polio vaccine (OPV) only. Despite global vaccine shortages, which limited countries' abilities to access IPV in a timely manner, 105 of 126 countries using OPV only introduced IPV within a 2.5-year period, making it the fastest rollout of a new vaccine in history. This achievement can be attributed to several factors, including the coordination work of the IMG; high-level engagement and advocacy across partners; the strong foundations of the Expanded Programme on Immunization at all levels; Gavi, the Vaccine Alliance's vaccine introduction experiences and mechanisms; innovative approaches; and proactive communications. In many ways, the IMG's work on IPV introduction can serve as a model for other vaccine introductions, especially in an accelerated context.

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The Public Health Legacy of Polio Eradication in Africa

Abstract
The legacy of polio in Africa goes far beyond the tragedies of millions of children with permanent paralysis. It has a positive side, which includes the many well-trained polio staff who have vaccinated children, conducted surveillance, tested stool specimens in the laboratories, engaged with communities, and taken care of polio patients. This legacy also includes support for routine immunization services and vaccine introductions and campaigns for other diseases. As polio funding declines, it is time to take stock of the resources made available with polio funding in Africa and begin to find ways to keep some of the talented staff, infrastructure, and systems in place to work on new public health challenges. The partnerships that helped support polio eradication will need to consider funding to maintain and to strengthen routine immunization services and other maternal, neonatal, and child health programs in Africa that have benefitted from the polio eradication infrastructure.

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Administering Multiple Injectable Vaccines During a Single Visit—Summary of Findings From the Accelerated Introduction of Inactivated Polio Vaccine Globally

Abstract
Background.
In 2013, the World Health Organization's (WHO's) Strategic Advisory Group of Experts (SAGE) recommended that all 126 countries using only oral polio vaccine (OPV) introduce at least 1 dose of inactivated polio vaccine (IPV) into their routine immunization schedules by the end of 2015. In many countries, the addition of IPV would necessitate delivery of multiple injectable vaccines (hereafter, "multiple injections") during a single visit, with infants receiving IPV alongside pentavalent vaccine (which covers diphtheria, tetanus, and whole-cell pertussis; hepatitis B; and Haemophilus influenzae type b) and pneumococcal vaccine. Unanticipated concerns emerged from countries over acceptability of multiple injections, sites of administration, and safety. We contextualized the issues surrounding multiple injections by documenting concerns associated with administration of ≥3 injections, existing evidence in the published literature, and findings of a systematic review on administration practices and techniques.
Methods.
Concerns associated with multiple-injection visits were documented from meetings and personal communications with immunization program managers. Published literature on the acceptability of multiple injections by providers and caregivers was summarized, and a systematic review of the literature on administration practices was completed on the following topics: spacing between injection sites (ie, vaccine spacing), site of injection, route of injection, and procedural preparedness. WHO and United Nations Children's Fund data from 2013–2015 were used to assess multiple-injection visits included in national immunization schedules.
Results.
Healthcare provider and caregiver attitudes and practices indicated concerns about infant pain, potential adverse effects, and uncertainty about vaccine effectiveness with multiple-injection visits. Published literature reinforced the record of safety and acceptance of the recommended schedule of IPV by the SAGE, but the evidence was largely from developed countries. Parental acceptance of multiple injections was associated with a positive provider recommendation to the caregiver. Findings of the systematic review identified that the intramuscular route is preferred over the subcutaneous route for vaccine administration and that the vastus lateralis muscle is preferred over the deltoid muscle for intramuscular injections. Recommendations on vaccine spacing and procedural preparedness were based on practical necessities, but comparative evidence was not identified. During 2013–2015, 85 countries added IPV to their immunization schedules, 46 (55%) of which adopted a schedule resulting in 3 injectable vaccines being administered in a single visit.
Conclusion.
The multiple-injection experience identified gaps in guidance for future vaccine introductions. Global partner organizations quickly mobilized to assess, document, and communicate the existing global experience on multiple-injection visits. This evidence-based approach provided reassurance to opinion leaders, health workers, and professional societies, thus encouraging uptake of IPV as a second or third injection in an accelerated manner globally.

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Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization

Abstract
A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette–Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities.

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Introduction of Inactivated Polio Vaccine, Withdrawal of Type 2 Oral Polio Vaccine, and Routine Immunization Strengthening in the Eastern Mediterranean Region

Abstract
The Global Polio Eradication Initiative has reduced the global incidence of polio by 99% and the number of countries with endemic polio from 125 to 3 countries. The Polio Eradication and Endgame Strategic Plan 2013–2018 (Endgame Plan) was developed to end polio disease. Key elements of the endgame plan include strengthening immunization systems using polio assets, introducing inactivated polio vaccine (IPV), and replacing trivalent oral polio vaccine with bivalent oral polio vaccine ("the switch"). Although coverage in the Eastern Mediterranean Region (EMR) with the third dose of a vaccine containing diphtheria, tetanus, and pertussis antigens (DTP3) was ≥90% in 14 countries in 2015, DTP3 coverage in EMR dropped from 86% in 2010 to 80% in 2015 due to civil disorder in multiple countries. To strengthen their immunization systems, Pakistan, Afghanistan, and Somalia developed draft plans to integrate Polio Eradication Initiative assets, staff, structure, and activities with their Expanded Programmes on Immunization, particularly in high-risk districts and regions. Between 2014 and 2016, 11 EMR countries introduced IPV in their routine immunization program, including all of the countries at highest risk for polio transmission (Afghanistan, Pakistan, Somalia, and Yemen). As a result, by the end of 2016 all EMR countries were using IPV except Egypt, where introduction of IPV was delayed by a global shortage. The switch was successfully implemented in EMR due to the motivation, engagement, and cooperation of immunization staff and decision makers across all national levels. Moreover, the switch succeeded because of the ability of even the immunization systems operating under hardship conditions of conflict to absorb the switch activities.

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Lessons From Globally Coordinated Cessation of Serotype 2 Oral Poliovirus Vaccine for the Remaining Serotypes

Abstract
Background.
Comparing model expectations with the experience of oral poliovirus vaccine (OPV) containing serotype 2 (OPV2) cessation can inform risk management for the expected cessation of OPV containing serotypes 1 and 3 (OPV13).
Methods.
We compare the expected post-OPV2-cessation OPV2-related viruses from models with the evidence available approximately 6 months after OPV2 cessation. We also model the trade-offs of use vs nonuse of monovalent OPV (mOPV) for outbreak response considering all 3 serotypes.
Results.
Although too early to tell definitively, the observed die-out of OPV2-related viruses in populations that attained sufficiently intense trivalent OPV (tOPV) use prior to OPV2 cessation appears consistent with model expectations. As expected, populations that did not intensify tOPV use prior to OPV2 cessation show continued circulation of serotype 2 vaccine-derived polioviruses (VDPVs). Failure to aggressively use mOPV to respond to circulating VDPVs results in a high risk of uncontrolled outbreaks that would require restarting OPV.
Conclusions.
Ensuring a successful endgame requires more aggressive OPV cessation risk management than has occurred to date for OPV2 cessation. This includes maintaining high population immunity to transmission up until OPV13 cessation, meeting all prerequisites for OPV cessation, and ensuring sufficient vaccine supply to prevent and respond to outbreaks.

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Impact of an Intervention to Use a Measles, Rubella, and Polio Mass Vaccination Campaign to Strengthen Routine Immunization Services in Nepal

Abstract
Background.
The potential to strengthen routine immunization (RI) services through supplementary immunization activities (SIAs) is an important benefit of global measles and rubella elimination and polio eradication strategies. However, little evidence exists on how best to use SIAs to strengthen RI. As part the 2012 Nepal measles-rubella and polio SIA, we developed an intervention package designed to improve RI processes and evaluated its effect on specific RI process measures.
Methods.
The intervention package was incorporated into existing SIA activities and materials to improve healthcare providers' RI knowledge and practices throughout Nepal. In 1 region (Central Region) we surveyed the same 100 randomly selected health facilities before and after the SIA and evaluated the following RI process measures: vaccine safety, RI planning, RI service delivery, vaccine supply chain, and RI data recording practices. Data collection included observations of vaccination sessions, interviews with the primary healthcare provider who administered vaccines at each facility, and administrative record reviews. Pair-matched analytical methods were used to determine whether statistically significant changes in the selected RI process measures occurred over time.
Results.
After the SIA, significant positive changes were measured in healthcare provider knowledge of adverse events following immunization (11% increase), availability of RI microplans (+17%) and maps (+12%), and awareness of how long a reconstituted measles vial can be used before it must be discarded (+14%). For the SIA, 42% of providers created an SIA high-risk villages list, and >50% incorporated this information into RI outreach session site planning. Significant negative changes occurred in correct knowledge of measles vaccination contraindications (−11%), correct definition for a measles outbreak (−21%), and how to treat a child with a severe adverse event following immunization (−10%). Twenty percent of providers reported cancelling ≥1 RI sessions during the SIA. Many RI process measures were at high proportions (>90%) before the SIA and remained high afterward, including proper vaccine administration techniques, proper vaccine waste management, and availability of vaccine carriers and vaccine registers.
Conclusions.
Focusing on activities that are easily linked between SIAs and RI services, such as using SIA high-risk village list to strengthen RI microplanning and examining ways to minimize the impact of an SIA on RI session scheduling, should be prioritized when implementing SIAs.

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Lessons From the Polio Endgame: Overcoming the Failure to Vaccinate and the Role of Subpopulations in Maintaining Transmission

Abstract
Background.
Recent detections of circulating serotype 2 vaccine-derived poliovirus in northern Nigeria (Borno and Sokoto states) and Pakistan (Balochistan Province) and serotype 1 wild poliovirus in Pakistan, Afghanistan, and Nigeria (Borno) represent public health emergencies that require aggressive response.
Methods.
We demonstrate the importance of undervaccinated subpopulations, using an existing dynamic poliovirus transmission and oral poliovirus vaccine evolution model. We review the lessons learned during the polio endgame about the role of subpopulations in sustaining transmission, and we explore the implications of subpopulations for other vaccine-preventable disease eradication efforts.
Results.
Relatively isolated subpopulations benefit little from high surrounding population immunity to transmission and will sustain transmission as long as they do not attain high vaccination coverage. Failing to reach such subpopulations with high coverage represents the root cause of polio eradication delays. Achieving and maintaining eradication requires addressing the weakest links, which includes immunizing populations in insecure areas and/or with disrupted or poor-performing health systems and managing the risks of individuals with primary immunodeficiencies who can excrete vaccine-derived poliovirus long-term.
Conclusions.
Eradication efforts for vaccine-preventable diseases need to create performance expectations for countries to immunize all people living within their borders and maintain high coverage with appropriate interventions.Keywords. Polio; eradication; transmission; heterogeneity.

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Using Acute Flaccid Paralysis Surveillance as a Platform for Vaccine-Preventable Disease Surveillance

Abstract
Surveillance for acute flaccid paralysis (AFP) is a fundamental cornerstone of the global polio eradication initiative (GPEI). Active surveillance (with visits to health facilities) is a critical strategy of AFP surveillance systems for highly sensitive and timely detection of cases. Because of the extensive resources devoted to AFP surveillance, multiple opportunities exist for additional diseases to be added using GPEI assets, particularly because there is generally 1 district officer responsible for all disease surveillance. For this reason, integrated surveillance has become a standard practice in many countries, ranging from adding surveillance for measles and rubella to integrated disease surveillance for outbreak-prone diseases (integrated disease surveillance and response). This report outlines the current level of disease surveillance integration in 3 countries (Nepal, India, and Nigeria) and proposes that resources continue for long-term maintenance in resource-poor countries of AFP surveillance as a platform for surveillance of vaccine-preventable diseases and other outbreak-prone diseases.

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Considerations for the Full Global Withdrawal of Oral Polio Vaccine After Eradication of Polio

Abstract
Eliminating the risk of polio from vaccine-derived polioviruses is essential for creating a polio-free world, and eliminating that risk will require stopping use of all oral polio vaccines (OPVs) once all types of wild polioviruses have been eradicated. In many ways, the experience with the global switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) can inform the eventual full global withdrawal of OPV. Significant preparation will be needed for a thorough, synchronized, and full withdrawal of OPV, and such preparation would be aided by setting a reasonably firm date for OPV withdrawal as far in advance as possible, ideally at least 24 months. A shorter lead time would provide valuable flexibility for decisions about when to stop use of OPV in the context of uncertainty about whether or not all types of wild polioviruses had been eradicated, but it might increase the cost of OPV withdrawal.

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Underlying maternal infection likely cause of study findings [Letters]



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Family physicians support Open Pharma [News]



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Postpartum hypertension [Practice]



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Delivering timely surgery in Canadian hospitals [Commentary]



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The authors respond to "Underlying maternal infection likely cause of study findings" [Letters]



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Spoon versus knife [Humanities]



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Using thermography responsibly [Letters]



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Pulling together [Coda]



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Functional Neurology



The past and future of Functional Neurology
D'Angelo E., Boller F., Wheeler-Kingshott C.G., Vanacore N., Sandrini G., Cisari C., Tamburin S., Baricich A.
doi: 10.11138/FNeur/2017.32.2.061
European core curriculum in neurorehabilitation
Sandrini G., Binder H., Hömberg V., Saltuari L., Tarkka I., Smania N., Corradini C., Giustini A., Kätterer C., Picari L., Diserens K., Koenig E., Geurts A., Anghelescu A., Opara J., Tonin P., Kwakkel G., Golyk V., Onose G., Pérennou D., Picelli A.
doi: 10.11138/FNeur/2017.32.2.063
Object decision and multiple sclerosis: a preliminary study
Caputi N., Matrella A., Totaro R., Raparelli C., Pontecorvo S., Di Giacomo D., Passafiume D.
doi: 10.11138/FNeur/2017.32.2.069
Cerebellar transcranial static magnetic field stimulation transiently reduces cerebellar brain inhibition
Matsugi A., Okada Y.
doi: 10.11138/FNeur/2017.32.2.077
HLA-DRB1*15 association with multiple sclerosis is confirmed in a multigenerational Italian family
Mosca L., Mantero V., Penco S., La Mantia L., De Benedetti S., MArazzi M.R., Spreafico C., Erminio C., Grassi L., Lando G., Zagaria M., Agostoni E., Protti A.
doi: 10.11138/FNeur/2017.32.2.083
The Italian real-life post-stroke spasticity survey: unmet needs in the management of spasticity with botulinum toxin type A
Picelli A., Baricich A., Cisari C., Paolucci S., Smania N., Sandrini G.
doi: 10.11138/FNeur/2017.32.2.089
Sensitivity of multi-shell NODDI to multiple sclerosis white matter changes: a pilot study
Schneider T., Brownlee W., Zhang H., Ciccarelli O., Miller D.H., Wheeler-Kingshott C.G.
doi: 10.11138/FNeur/2017.32.2.097
Ixcellence Network®: an international educational network to improve current practice in themanagement of cervical dystonia or spastic paresis by botulinum toxin injection
Fheodoroff K., Bhidayasiri R., Jacinto L.J., Chung T.M., Bhatia K., Landreauf T., Colosimo C.
doi: 10.11138/FNeur/2017.32.2.103


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Cancer risk among Holocaust survivors in Israel—A nationwide study

BACKGROUND

Holocaust survivors during World War II were exposed to various factors that are associated with cancer risk. The objective of this study was to determine whether Holocaust survivors had an increased risk for developing cancer.

METHODS

The study population included 152,622 survivors. The main analysis was based on a comparison between individuals who were entitled to compensation for suffering persecution during the war and individuals who were denied such compensation. A complementary analysis compared survivors who were born in countries governed by Nazi Germany with survivors born in nonoccupied countries. A Cox proportional hazards model was used, with the time at risk of cancer development starting on either January 1, 1960, or the date of immigration to the date of cancer diagnosis or death or the date of last follow-up (December 31, 2006).

RESULTS

Cancer was diagnosed in 22.2% of those who were granted compensation versus 16% of those who were denied compensation (P < .0001). Adjusting for birth cohort, sex, country of origin, and period of immigration, both analyses revealed significant increased risks of developing cancer in those who were exposed. For those who were granted versus denied compensation, the hazard ratios were 1.06 (P < .001) for all sites, 1.12 (P = .07) for colorectal cancer, and 1.37 (P = .008) for lung cancer. For those born in occupied countries versus nonoccupied countries, the hazard ratios were 1.08 (P < .001), 1.08 (P = .003), and 1.12 (P = .02), respectively.

CONCLUSIONS

The current results, based on a large cohort of Holocaust survivors who were exposed to a variety of severe deprivations, add to the conflicting and sparse knowledge on this issue and support the notion that this group has a small but consistent increase in cancer development. [See related editorial on pages 000-000, this issue.] Cancer 2017. © 2017 American Cancer Society.



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Extreme population-level events: Do they have an impact on cancer?

The report by Sadetzki and colleagues in this issue showcases the impact of a horrendous event—the Holocaust—on subsequent health decades after the occurrence. Two additional calamities—country-wide famines and population-level discrimination—are provided as examples of this phenomenon to add evidence to the causal pathway identified by Sadetzki et al. See also pages 000-000.



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High level of tobacco carcinogen-derived DNA damage in oral cells is an independent predictor of oral/head and neck cancer risk in smokers

High level of tobacco carcinogen-derived DNA damage in oral cells is an independent predictor of oral/head and neck cancer risk in smokers:

Exposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is recognized to play an important role in the development of oral/head and neck squamous cell cancer (HNSCC).  We recently reported higher levels of TSNA-associated DNA adducts in the oral cells of smokers with HNSCC as compared to cancer-free smokers.  In this study we further investigated the tobacco constituent exposures in the same smokers to better understand the potential causes for the elevated oral DNA damage in smokers with HNSCC.  Subjects included cigarette smokers with HNSCC (Cases, n=30) and cancer-free smokers  (Controls, n=35). At recruitment, tobacco/alcohol use questionnaires were completed, urine and oral cell samples were obtained. Analysis of urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and N'-Nitrosonornicotine (NNN) (TSNA biomarkers), 1-hydroxypyrene (1-HOP, a PAH), cotinine, 3'-hydroxycotinine and the nicotine metabolite ratio (NMR) were performed.  Cases and controls differed in mean age, male preponderance and frequency of alcohol consumption (but not total alcoholic drinks).  Univariate analysis revealed similar levels of NNN, 1-HOP and cotinine between groups but, as reported previously, significantly higher DNA adduct formation in the cases.  Multiple regression adjusting for potential confounders showed persistent significant difference in DNA adduct levels between cases and controls (ratio of geometric means: 20.0 (95% CI=2.7-148.6)).  Our cohort of smokers with HNSCC demonstrates higher levels of TSNA-derived oral DNA damage in the setting of similar exposure to nicotine and tobacco carcinogens.  Among smokers, DNA adduct formation may act as a predictor of eventual development of HNSCC that is independent of carcinogen exposure indicators.



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Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan

Characteristics of adverse drug reactions in a vemurafenib early post-marketing phase vigilance study in Japan:

Abstract



Background

Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study.




Methods

ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown. ADR data were collected for patients treated with vemurafenib (960 mg bid) between 26 February and 25 August 2015.




Results

Among 95 patients, 46 patients had 118 ADRs (24 serious ADRs in 13 patients). The most common serious ADRs were hypersensitivity (n = 1; 3 events), arthralgia (n = 2; 2 events), pyrexia (n = 2; 2 events) and drug eruption (n = 2; 2 events). Seven patients had serious skin disorders or hypersensitivity, six of whom had prior anti-programmed cell death-1 (PD-1) antibodies 5–35 days before starting vemurafenib. ADR reports of serious skin disorders appeared to be collected more rapidly than previously reported. Cutaneous squamous cell carcinoma developed in only one patient.




Conclusions

EPPV in Japanese vemurafenib-treated patients identified no new safety signals. The most serious skin and hypersensitivity ADRs occurred in patients with prior anti-PD-1 exposure. Cutaneous squamous cell carcinoma appeared to be rare in Japanese patients. Further research is needed to clarify whether prior treatment with anti-PD-1 agents or racial differences affect the characteristic profile of cutaneous ADRs in Japanese patients.



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Selection of DNA aptamers for extra cellular domain of human epidermal growth factor receptor 2 to detect HER2 positive carcinomas

Selection of DNA aptamers for extra cellular domain of human epidermal growth factor receptor 2 to detect HER2 positive carcinomas:

Abstract



Background

Human epidermal growth factor receptor 2 (Her2, an orphan receptor of ErbB family) is considered as an important biomarker as it plays a key role in the development and progression of aggressive types of breast, ovarian, stomach and gastric cancer. In the present study, we developed novel DNA aptamers against the extra-cellular domain (ECD) of Her2 protein for detection of Her2-positive carcinomas.




Methods

We cloned and expressed Her2–ECD protein in E. coli system. After purification, the protein was used as a bait for screening of specific DNA aptamer candidate from a pool of 1014–15 random oligonucleotides through in vitro Systematic Evaluation of Ligands by Exponential Enrichment (SELEX) process. The aptamer–protein binding kinetics was elucidated by isothermal calorimetry. The specificity of FAM-labelled ECD_Apt1 towards Her2-positive cell lines was estimated by FACS and immunofluorescence assay. The specificity of the candidate was also verified with the tissue samples of breast cancer patients by immunohistochemistry process.




Results

Among four selected candidates, ECD_Apt1 (having minimum ∆G = −3.24) showed the highest binding affinity (K
d = 6.33 ± 0.86 nM) to Her2–ECD protein. The aptamer–protein sandwich assay showed a linear rise in chemiluminescence (at 490 nm wavelength) in the dynamic range of 100−700 nM ECD_Apt1 with a detection limit of 12.5 ± 2.5 ng/mL. Biotinylated ECD_Apt1 showed stronger cytoplasmic staining in Her2-positive breast cancer cell lines (SKBR3) compared to Her2-negative cells (MDA MB 231, MCF7). In paraffin-embedded breast cancer tissue sections, it showed specific and selective localization in the cytoplasmic niche of malignant duct cancer cells without any cross-reactivity to fibroblasts, inflammatory cells and adipocytes.




Conclusions

Binding assays, cytochemical and histochemical studies support ECD_Apt1 as a potential theranostic agent for Her2-positive carcinomas. ECD_Apt1 could be an effective low-cost alternative to conventional anti-Her2 antibody in solid phase immunoassays for cancer diagnosis and related applications.



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FOTROCAN Delphi consensus statement regarding the prevention and treatment of cancer-associated thrombosis in areas of uncertainty and low quality of evidence

FOTROCAN Delphi consensus statement regarding the prevention and treatment of cancer-associated thrombosis in areas of uncertainty and low quality of evidence:

Abstract



Introduction

Decision-making in cancer-related venous thromboembolism (VTE) is often founded on scant lines of evidence and weak recommendations. The aim of this work is to evaluate the percentage of agreement surrounding a series of statements about complex, clinically relevant, and highly uncertain aspects to formulate explicit action guidelines.




Materials and methods

Opinions were based on a structured questionnaire with appropriate scores and were agreed upon using a Delphi method. Questions were selected based on a list of recommendations with low evidence from the Spanish Society of Oncology Clinical Guideline for Thrombosis. The questionnaire was completed in two iterations by a multidisciplinary panel of experts in thrombosis.




Results

Of the 123 statements analyzed, the panel concurred on 22 (17%) and another 81 (65%) were agreed on by qualified majority, including important aspects of long-term and prolonged anticoagulation, major bleeding and rethrombosis management, treatment in special situations, catheter-related thrombosis and thromboprophylaxis. Among them, the panelists agreed the incidental events should be equated to symptomatic ones, long-term and extended use of full-dose low-molecular weight heparin, and concluded that the Khorana score is not sensitive enough to uphold an effective thromboprophylaxis strategy.




Conclusion

Though the level of consensus varied depending on the scenario presented, overall, the iterative process achieved broad agreement as to the general treatment principles of cancer-associated VTE. Clinical validation of these statements in genuine practice conditions would be useful.



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Hearing Preservation and Bimodal Listening

20Q: Combining Electric and Acoustic Hearing - Hearing Preservation and Bimodal Listening:

From the Desk of Gus Mueller

It seems that each year, the audiometric definition of who might be a cochlear implant candidate becomes broader. And, cochlear implant technology also is rapidly changing. In recent years we have seen improved form factors, more advanced signal classification and processing, and increased wireless connectivity options. Another area where advancements have been observed recently is with the hybrid cochlear implant systems, that is, systems with combined electric and acoustic stimulation (EAS).

Discussion of EAS systems is not totally new to 20Q. Back in June 2011, Dr. René Gifford joined us to describe this technology, and reviewed what was then "new" research (you can read that article here). But that was six years ago, and a lot has changed, so we thought it was time to invite René back to provide us with an update.

René Gifford, Ph.D, is a Professor in the Vanderbilt Department of Hearing and Speech Sciences with a joint appointment in the Department of Otolaryngology. She is currently the Director of the Cochlear Implant Program at the Vanderbilt Bill Wilkerson Center in the Division of Audiology as well as the Director of the Cochlear Implant Research Laboratory. Dr. Gifford is one of the leading researchers in the area of cochlear implants with over 100 publications and numerous book chapters on this topic. In addition, she has authored the popular clinically-based book, Cochlear Implant Patient Assessment: Evaluation of Candidacy, Performance, and Outcomes.

Dr. Gifford currently is the principal investigator on two NIH grants centered on cochlear implants. In addition to her research interests with EAS systems, she also is studying preoperative prediction of postoperative outcomes, speech perception for adults and children with cochlear implants, and spatial hearing abilities of individuals with unilateral and bilateral cochlear implants.

René's national acclaim has led to her receiving the ASHA Award for Clinical Achievement, and recently she was the featured scientist for the NPR Science Friday broadcast. It's always nice to hear the latest advancements on a topic from an expert, so sit back and enjoy this month's 20Q!

Gus Mueller, PhD
Contributing Editor
July 2017

Browse the complete collection of 20Q with Gus Mueller CEU articles at http://ift.tt/2uHfvS0
20Q: Combining Electric and Acoustic Hearing - Hearing Preservation and Bimodal Listening​


Learning Outcomes
After this course, readers will be able to:

Define EAS/Hybrid implant system and explain the differences from a traditional cochlear implant.
Explain the general indications for an EAS/Hybrid system, and list the potential benefits of such a system, based on the evidence.
Explain the benefits of bimodal listening as well as hearing preservation for CI recipients.
Describe the role that ITD sensitivity plays in EAS/Hybrid benefit.
Discuss the general approach for programming EAS/Hybrid systems, including new evidence for optimizing outcomes, and explain how the acoustic component is typically fit.

René Gifford

1. It's been a while since we last spoke with you here at 20Q. We were last talking about hybrid cochlear implant systems, if I recall correctly?

Yes, it's been over 6 years since our last 20Q on the topic of hybrid cochlear implant (CI) systems, also referred to as combined electric and acoustic stimulation (EAS) systems. For a brief refresher, EAS/Hybrid devices are implanted using minimally traumatic surgical techniques with thinner, less traumatic electrode arrays. In the best-case scenario, there is minimal surgical trauma to the delicate intracochlear structures with the goal of preserving residual low frequency acoustic hearing to be combined in an EAS/Hybrid listening configuration. Hearing preservation surgery can be achieved with essentially any cochlear implant device and electrode type available in the US today.

A lot has changed in just the past few years. For example, we now have two FDA-approved EAS/Hybrid systems that use integrated EAS processors. This means that the CI processor is capable of providing both electric stimulation and acoustic amplification for the implanted ear. This has made our job so much simpler for the population of patients who already have hearing preservation and for the rapidly growing population of newly implanted CI recipients with hearing preservation!

2. Integrated EAS processors? What did you do before these integrated sound processors were available?

For patients with significant residual hearing in the implanted ear, we would often fit an in-the-ear (ITE) hearing aid (HA) to be worn in the implanted ear along with the behind-the-ear (BTE) CI sound processor. We had some patients who used an off-the-ear CI processor (such as the MED-EL Rondo, Advanced Bionics Neptune, or more recently, the Cochlear Kanso) that allowed the patient to continue use of the BTE HA in the implanted ear. But realistically, even the patients who were fitted with hearing aids and who demonstrated benefit from hearing preservation were reluctant to wear three or even four separate hearing devices—the latter relevant for bilateral CI recipients with bilateral acoustic hearing preservation. It just wasn't a practical, everyday solution.

3. I recall that you mentioned that some EAS patients fail to demonstrate significant benefit from the preserved hearing in the implanted ear. Is that why some patients were reluctant to wear up to four devices?

That's correct, but with a very big caveat. Clinical assessment of speech understanding is generally achieved using a single loudspeaker placed directly in front of the listener. So, if you compare the best-aided EAS condition (CI + bilateral HAs) to the bimodal control condition (CI + contralateral HA), the best we could expect are just a few percentage points afforded by summation of bilateral low-frequency acoustic hearing. Recall that the typical auditory profile for EAS and Hybrid CI recipients is that of a bilateral precipitously sloping high-frequency hearing loss. What that means is that the summation effects that we could measure in the clinical environment will be reduced given the restricted audible bandwidth in the acoustic hearing ears. There are very few patients who fail to demonstrate at least some benefit of aiding residual hearing in the implanted ear. But I am really only referring to those individuals who have aidable hearing in the low frequency region (low frequency thresholds in the 70 to 80 dB HL range).

4. What would be the better way to assess benefit for EAS patients in the audiology clinic?

Well, there really might not be an ideal metric for the typical audiology clinic. For CI recipients, we do not reference binaural hearing for a few reasons. First, CI sound processors do not currently afford recipients access to the interaural time difference (ITD) cues given the use of a constant, high-rate stimulation with a pulse train that is amplitude modulated by the envelope of each band-pass filter. Second, the CI sound processors have automatic gain control (AGC) features, which are highly necessary due to the narrow electric dynamic range. However, these AGC features attenuate interaural level differences (ILDs) rendering these cues useful but significantly reduced relative to individuals with normal hearing, or even relative to individuals with hearing loss using amplification with less input compression (e.g., Grantham, Ashmead, Ricketts, Haynes, & Labadie, 2008). EAS/Hybrid CI recipients with hearing preservation in the implanted ear(s) have binaural hearing in the low-to-mid frequencies—or at least over the range of audibility for both ears. Thus, there are several potential benefits of having access to ITDs, but few that could be assessed in a typical clinical environment.

The first and most robust benefit is in localization, which is significantly improved by providing the CI recipient with binaural acoustic hearing (e.g., Dunn, Perreau, Gantz, & Tyler, 2010; Gifford et al., 2014a, 2014b; Dorman, Loiselle, Cook, Yost, & Gifford, 2016; Loiselle, Dorman, Yost, & Gifford, 2015). The second benefit is in speech understanding in complex listening environments, such as those that include diffuse noise and/or reverberation. Having access to ITDs can really benefit a listener in the latter environment. That is, the listener is typically looking at the talker which should provide a 0-microsecond ITD for the speech stimulus; on the other hand, the distracting noise sources reach the ears at various different ITDs allowing for binaural unmasking of speech—also commonly referred to as binaural squelch. This is, of course, assuming that the CI recipients have ITD sensitivity.

5. Has anyone tested whether these implant recipients actually have ITD sensitivity?

In fact, we measured ITD thresholds for 14 adult CI recipients with hearing preservation as well as 5 listeners with normal hearing (Gifford et al., 2013, 2014b). We found that ITD sensitivity was highly variable for the CI recipients with thresholds rivaling those of normal hearing listeners up to ITD thresholds that are not physiologically relevant (> 700-800 microseconds). Not surprisingly, we also found that ITD thresholds were significantly correlated with localization accuracy as well as the degree of EAS/Hybrid benefit obtained by adding acoustic hearing from the implanted ear for speech understanding in a semi-diffuse, restaurant noise background. So it does appear that ITD sensitivity plays a major role in this EAS/Hybrid benefit.

6. Was it the case that those who had the best hearing preservation also had the best ITD thresholds?

That's close to correct, but rather it was the degree of symmetry in low frequency thresholds that was correlated with ITD sensitivity, not simply the auditory thresholds in the implanted ear. The reason that it is not simply defined by detection thresholds in the implanted ear is that the thresholds in the non-implanted ear are also relevant—it's the interaural component that is important in ITDs. Or, as I often say, remember the "I" in ITD. In a later paper, we demonstrated significantly better localization for hearing preservation implant recipients with symmetrical low frequency audiometric thresholds (0 to 15 dB interaural asymmetry) as compared to those with highly asymmetric audiometric thresholds (45 to 60 dB interaural asymmetry, on average) (Loiselle et al., 2015).

7. What kind of speech recognition benefit are we seeing these days for EAS/Hybrid recipients?

Reports in the literature demonstrate average speech recognition benefit from preserved acoustic hearing in the implanted ear from 10 to over 20 percentage points or approximately 2 dB, up to 5 dB improvement in the signal-to-noise ratio (SNR) (e.g., Dunn et al., 2010; Dorman & Gifford, 2010; Dorman, Spahr, Gifford, Cook, & Zhang, 2012; Dorman et al., 2013; Gifford, Dorman, & Brown, 2010; Gifford et al., 2012, 2013, 2014a, 2014b, 2017; Rader, Fastl, & Baumann, 2013). This might not seem like much, but remember, this benefit of 10 to 20 percentage points (or 2 to 5 dB in the SNR) is above and beyond the performance obtained in the bimodal hearing configuration (CI + contralateral HA). Furthermore, we recently demonstrated that perceived listening difficulty is significantly reduced for individuals using binaural low-frequency acoustic hearing as compared to just monaural acoustic hearing.

8. Doesn't bimodal hearing also offer significant benefit?

Yes, you are absolutely correct! Adding a HA in the non-implanted ear—for a bimodal hearing configuration—provides significant benefit for speech understanding in quiet and in background noise. In fact, adding a hearing aid in the non-implanted ear yields improvement of 1020% for speech in quiet (e.g., Dunn, Tyler, & Witt, 2005; Gifford, Dorman, Spahr, & McKarns, 2007; van Hoesel, 2012; Illg, Bojanowicz, Lesinski-Schiedat, Lenarz, & Büchner, 2014) and 15 to over 40 percentage points for speech recognition in noise (e.g., van Hoesel, 2012; Sheffield & Gifford, 2014; Zhang, Dorman, & Spahr, 2010; Zhang, Dorman, Gifford, & Moore, 2014). Bimodal listening, however, offers little improvement for horizontal plane localization (e.g., Potts, Skinner, Litovsky, Strube, & Kuk, 2009; Dorman et al., 2016). The primary reason is that localization is achieved by comparing ITDs and/or ILDs. Most adult bimodal listeners have precipitously sloping, high frequency hearing loss. Thus, there is no possibility of access to ILDs which are predominantly located in the higher frequency region. Further, timing information is available in the non-implanted ear, but periodicity and fine structure cues are not well preserved by the CI. Thus, bimodal listeners do not have access to ITDs either, as they are missing cues in the implanted ear for an interaural comparison (again, they're missing the "I" in ITD).

9. Got it - though I couldn't help but notice that you specifically mentioned adults. Do children show different trends for bimodal hearing?

You caught that, huh? Though it is cliché, children really are not little adults. When we're talking about children with prelingual onset of hearing loss, auditory development is achieved through the use of hearing aids and/or cochlear implants. There are a couple of studies that have demonstrated significantly better bimodal localization for children than for adults with bimodal hearing (e.g., Davidson, Firszt, Brenner, & Cadieux, 2015; Choi et al., 2017). There is still much to be learned about children combining electric and acoustic hearing, however, one thing is certain - children absolutely derive bimodal benefit. Are you also curious about pediatric implant recipients with hearing preservation?

10. Sure - what do we know about hearing preservation with children?

There are reports of pediatric cochlear implant recipients with hearing preservation (e.g., Skarzynski, Lorens, Piotrowska, & Anderson, 2007, Skarzynski et al., 2016; Bruce et al., 2014; Carlson et al., 2017). Indeed, children exhibit similar levels of hearing preservation following cochlear implantation as those for adult recipients—specifically we see low frequency threshold elevation ranging from 10 to 20 dB, on average. We do not know, however, whether children with hearing preservation have access to low frequency ITD cues. Keep in mind that spatial hearing abilities continue to mature through adolescence, even for children with normal hearing. We have much to learn about this population. Also, it is important to mention that the current EAS/Hybrid cochlear implant systems are not indicated for use with children. These children, therefore, are currently implanted off-label, which is allowed per the FDA given the professional clinical judgment of the physician and implant team. However, use of EAS/Hybrid cochlear implant systems with children is much less prevalent than traditional CIs for pediatric implant recipients with bilateral profound sensorineural hearing loss. So, for the purposes of this discussion, we should focus on adult implant recipients.

11. Ok, then getting back to adults - can you give me a summary of how EAS/Hybrid devices are programmed?

How much time do you have? Seriously, this is a complicated answer and there is currently no consensus. In the past, the majority of patients were programmed using either complete EAS overlap or minimal EAS overlap in the implanted ear. That is, complete EAS overlap would allow for full CI bandwidth as well as full aidable bandwidth for acoustic amplification. Minimal EAS overlap would generally set the low frequency cutoff for the CI to the frequency at which audiometric thresholds reached 85 to 90 dB HL. For a summary of previous studies, see Table 1 in Gifford et al. (2017). While EAS/Hybrid patients exhibited significant benefit irrespective of the EAS overlap, we have more recent evidence to suggest that we might not have been optimizing outcomes for these patients.

12. What does the recent evidence suggest in terms of optimizing outcomes - can you elaborate?

Sure, the clinical software for clinical trials of the Hybrid-L24 system as well as the MED-EL EAS system had both used EAS cutoffs that provided acoustic amplification for frequencies with thresholds up to 85 to 90 dB HL, and then would set the low frequency CI cutoff to the limits of acoustic audibility—generally also the frequency at which audiometric thresholds reach 85 to 90 dB HL (NOTE: there was some variability in the algorithm depending on both the severity and the slope of the hearing loss). In a recent paper with 11 EAS/Hybrid recipient (13 ears), we found significantly better outcomes for speech understanding and perceived listening difficulty by setting the low frequency CI cutoff to the frequency at which the audiogram reached 70 dB HL (Gifford et al., 2017).

13. That's interesting. Do you have any explanation for why changing the low frequency CI cutoff had an impact on outcomes?

We have various theories. The primary theory is pretty simple. Recall that these patients met cochlear implant candidacy and pursued cochlear implantation. While they had considerable residual hearing in the low frequencies, it was not sufficient to offer high levels of speech understanding. Thus, we should likely not require that the EAS/Hybrid recipient rely too heavily on that low frequency acoustic hearing. In other words, providing more speech information through the CI with a broader CI bandwidth yields significantly higher speech understanding and less perceived listening difficulty. Paramount to this theory are a number of previous studies demonstrating diminishing benefit for acoustic amplification for spectral regions with audiometric thresholds reaching approximately 70 dB HL (e.g., Hogan & Turner, 1998; Ching et al., 1998; Turner & Cummings, 1999; Hornsby & Ricketts, 2003, 2006). Thus, we have theorized that setting the low frequency CI cutoff at the frequency where the audiogram reaches approximately 90 dB HL is likely placing too much weight on spectral regions where acoustic amplification may not be effective.

14. What do you think is going on with the underlying cochlear physiology for regions where thresholds reach or exceed 70 dB HL?

Research suggests that this is related to greater inner hair cell damage. We know that once hearing losses exceed approximately 60 dB that we have involvement of both outer and inner hair cells (Liberman & Dodds, 1984). Our inner hair cells are our primary sensory transducers (afferent innervation). That means that once inner hair cells are dysfunctional or destroyed, no amount or quality of acoustic amplification will be capable of driving auditory nerve fibers in that frequency region. This is the beauty of EAS/Hybrid systems! The recipient can still take advantage of the richer, more natural sound quality of the acoustic low frequency hearing and use electrical stimulation for the frequencies not well transmitted by conventional acoustic amplification.

15. Let's backtrack for just a moment. You mentioned that previous clinical trials used an EAS/Hybrid crossover that may not have been optimal. What does that mean for current and future EAS/Hybrid recipients?

Great question! The good news is that these parameters are easily manipulated in the clinical software for the EAS/Hybrid systems. I tend to believe that much of the benefit reported in research publications that we associated for hearing preservation cochlear implantation, while significant, may have been of a smaller magnitude than the patients' underlying auditory potential due to lack of optimized EAS/Hybrid parameters—this includes some of my own publications! Specifically, many of the previous studies used full EAS overlap or little-to-no EAS overlap. In our most recent paper (Gifford et al. 2017), we observed improvements in speech understanding that reached up to 20 percentage points beyond that offered by the full CI bandwidth or no EAS overlap. This was achieved simply by providing more EAS overlap by lowering the CI starting frequency. Based on these data, Cochlear has changed the default EAS/Hybrid crossover frequency to correspond to the frequency at which the audiogram reaches approximately 70 dB HL. It is very possible that we've been selling ourselves short on the magnitude of the EAS/Hybrid benefit that one could receive! We need more research to investigate the expected benefit with optimized HA and CI parameters based on patient-specific variables—like personalized or precision hearing healthcare.

16. Should all EAS/Hybrid patients be reprogrammed by lowering the CI starting frequency to where the audiogram reaches 70 dB HL?

I'm reluctant to make such a broad recommendation at this point. Keep in mind, we only tested 11 patients (13 ears). While the results were significant, we still have much to learn. I tend to recommend that we provide our patients with more than one program with different EAS/Hybrid crossover frequencies and then make decisions based on speech understanding outcomes and patient report. It is also likely that the insertion depth of the electrode array also plays a role. Today we have access to a variety of cochlear implant electrodes ranging from 16 mm up to 31 mm. There are various reports of hearing preservation with nearly all available electrodes on the market today. It's an exciting time to be a practicing audiologist!

17. I thought that hearing preservation was primarily limited to just the shorter electrodes. Are you saying that there are cochlear implant recipients with conventional electrodes who are using an EAS/Hybrid hearing configuration?

Yes, that is the case. If a patient has preserved acoustic hearing, we can fit them with an integrated EAS/Hybrid system irrespective of the implanted electrode array. Right now we can do this in the clinic for both Cochlear and MED-EL. Advanced Bionics is still in clinical trials with their EAS system.

18. How are audiologists fitting the acoustic component of the CI sound processor?

We use probe microphone measures for verification, of course! Right now we are fitting to NAL-NL2 (Keidser, Dillon, Carter, & O'Brien, 2012) targets for low frequencies in the implanted ear. For pediatric CI recipients with hearing preservation using an EAS/Hybrid hearing configuration, I would recommend using DSL v5 child targets (Scollie et al., 2005). It is quite possible that we might discover that an entirely different prescriptive fitting formula may be more appropriate for individuals combining electric and acoustic hearing in the same ear. For now, we going to leave this up to the hearing aid fitting experts and their decades of evidence-based recommendations.

19. Are there patients who have normal or near-normal hearing in the low frequencies who wouldn't require any acoustic amplification?

Ah yes, I didn't even mention this population. There are some patients who have normal to near-normal hearing in the low frequencies and then combine with electric stimulation in the mid-to-high frequencies. This is another population of interest as it might even be possible that based on low frequency hearing and electrode insertion depth, we could find different fitting recommendations.

20. It seems that the days of "hearing aid" audiologists and "cochlear implant" audiologists are slipping away. What do you think?

It is true that hearing aids and cochlear implants are increasingly merging and I believe we'll be seeing even greater integration of these technologies in the next few years. But, we still have a much greater population of individuals who are hearing aid candidates as compared to cochlear implant or EAS/Hybrid cochlear implant candidates. However, for those in-between patients who struggle with traditional amplification due to the severity of their high frequency hearing loss, but are generally performing too well with their hearing aids to qualify for a conventional CI, I suggest they be referred for a cochlear implant evaluation. We just might be able to help them!

References
Bruce, I.A., Felton, M., Lockley, M., Melling, C., Lloyd, S.K., Freeman, S.R., & Green, K.M. (2014). Hearing preservation cochlear implantation in adolescents. Otology & Neurotology, 35, 1552–9.

Carlson, M.L., Patel, N.S., Tombers, N.M., DeJong, M.D., Breneman, A.I., Neff, B.A., & Driscoll, C.L.W. (2017). Hearing preservation in pediatric cochlear implantation. Otology & Neurotology, 38(6), e128-e133. doi: 10.1097/MAO.0000000000001444

Choi, J.E., Moon, I.J., Kim, E.Y., Park, H.S., Kim, B.K., Chung, W.H.,...Hong, S.H. (2017). Sound localization and speech perception in noise of pediatric cochlear implant recipients: Bimodal fitting versus bilateral cochlear implants. Ear Hear., 38, 426-440.

Davidson, L.S., Firszt, J.B., Brenner, C., & Cadieux, J.H. (2015). Evaluation of hearing aid frequency response fittings in pediatric and young adult bimodal recipients. Journal of the Americal Academy of Audiology, 26, 393-407.

Dorman, M.F., & Gifford, R.H. (2010). Combining acoustic and electric stimulation in the service of speech recognition. International Journal of Audiology, 49, 912-919.

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Gifford, R.H., Davis, T.J., Sunderhaus, L.W., Menapace, C., Buck, B., Crosson, J.,…Segel, P. (2017). Combined electric and acoustic stimulation with hearing preservation: Effect of cochlear implant low-frequency cutoff on speech understanding and perceived listening difficulty. Ear Hear., [Epub ahead of print]. doi: 10.1097/AUD.0000000000000418

Gifford, R.H., Dorman, M.F., & Brown, C.A. (2010). Psychophysical properties of low-frequency hearing: implications for perceiving speech and music via electric and acoustic stimulation. Advances in Otorhinolaryngology, 67, 51-60.

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Citation
Gifford, R. (2017, July). 20Q: Combining electric and acoustic hearing - Hearing preservation and bimodal listening. AudiologyOnline, Article 20676. Retrieved from http://ift.tt/1nQruDo


René Gifford
René H. Gifford, Ph.D, CCC-A, is a Professor in the Department of Hearing and Speech Sciences with a joint appointment in the Department of Otolaryngology. She is currently the Director of the Cochlear Implant Program at the Vanderbilt Bill Wilkerson Center in the Division of Audiology as well as the Director of the Cochlear Implant Research Laboratory.

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The Clinical Evaluation of Angioedema.

The Clinical Evaluation of Angioedema.:

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The Clinical Evaluation of Angioedema.

Immunol Allergy Clin North Am. 2017 Aug;37(3):449-466

Authors: Gill P, Betschel SD

Abstract

The clinical evaluation of angioedema is reliant on obtaining a thorough patient and family history with an assessment of risk factors and presenting symptoms unique to each subtype. It is important to distinguish between angioedema with and without urticaria as a primary step in the evaluation; thereafter, laboratory parameters and investigations allow for subsequent stratification. There is a significant disease burden associated with angioedema and thus it is essential for health care practitioners to establish a prompt and accurate diagnosis, and a comprehensive care plan that addresses the patient's physical and mental well-being alike.

PMID: 28687102 [PubMed - in process]



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Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema.

Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema.:

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Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema.

Immunol Allergy Clin North Am. 2017 Aug;37(3):483-495

Authors: Stone C, Brown NJ

Abstract

Nonsteroidal antiinflammatory agents, β-lactam antibiotics, non-β lactam antibiotics, and angiotensin-converting enzyme inhibitors are the most common classes of drugs that cause angioedema. Drug-induced angioedema is known to occur via mechanisms mediated by histamine, bradykinin, or leukotriene, and an understanding of these mechanisms is crucial in guiding therapeutic decisions. Nonallergic angioedema occurs in patients with genetic variants that affect metabolism or synthesis of bradykinin, substance P, prostaglandins, or leukotrienes, or when patients are taking drugs that have synergistic mechanisms. The mainstay in treatment of nonallergic drug-induced angioedema is cessation of the offending agents.

PMID: 28687104 [PubMed - in process]



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Acquired C1 Inhibitor Deficiency.

Acquired C1 Inhibitor Deficiency.:

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Acquired C1 Inhibitor Deficiency.

Immunol Allergy Clin North Am. 2017 Aug;37(3):497-511

Authors: Otani IM, Banerji A

Abstract

Acquired angioedema due to C1-INH deficiency (C1-INH-AAE) can occur when there are acquired (not inherited) deficiencies of C1-INH. A quantitative or functional C1-INH deficiency with negative family history and low C1q is diagnostic of C1-INH-AAE. The most common conditions associated with C1-INH-AAE are autoimmunity and B-cell lymphoproliferative disorders. A diagnosis of C1-INH-AAE can precede a diagnosis of lymphoproliferative disease and confers an increased risk for developing non-Hodgkin lymphoma. Treatment focuses on symptom control with therapies that regulate bradykinin activity (C1-INH concentrate, icatibant, ecallantide, tranexamic acid, androgens) and treatment of any underlying conditions.

PMID: 28687105 [PubMed - in process]



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Laboratory Approaches for Assessing Contact System Activation.

Laboratory Approaches for Assessing Contact System Activation.:

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Laboratory Approaches for Assessing Contact System Activation.

Immunol Allergy Clin North Am. 2017 Aug;37(3):527-539

Authors: Christiansen SC, Zuraw BL

Abstract

Hereditary angioedema (HAE) is a rare autosomal dominant disease clinically characterized by recurrent, often unpredictable attacks of subcutaneous and mucosal swelling. Acute episodes are debilitating, painful, disfiguring, and potentially fatal. HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. HAE with normal levels of C1 inhibitor has been recognized. There is evidence that contact activation underlies the recurrent attacks of swelling. This article reviews laboratory parameters to detect contact system activation and implications for diagnosis of HAE and other forms of bradykinin-mediated angioedema.

PMID: 28687107 [PubMed - in process]



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Prophylactic Therapy for Hereditary Angioedema.

Prophylactic Therapy for Hereditary Angioedema.:

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Prophylactic Therapy for Hereditary Angioedema.

Immunol Allergy Clin North Am. 2017 Aug;37(3):557-570

Authors: Longhurst H, Zinser E

Abstract

Long-term prophylaxis is needed in many patients with hereditary angioedema and poses many challenges. Attenuated androgens are effective in many but are limited by side effect profiles. There is less evidence for efficacy of tranexamic acid and progestagens; however, the small side effect profile makes tranexamic acid an option for prophylaxis in children and progestagens an option for women. C1 inhibitor is beneficial, but at present requires intravenous delivery and may need dose titration for maximum efficacy. Short-term prophylaxis should be considered for all procedures. New therapies are promising in overcoming many problems encountered with current options for long-term prophylaxis.

PMID: 28687109 [PubMed - in process]



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Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment.

Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment.:

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Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment.

Immunol Allergy Clin North Am. 2017 Aug;37(3):571-584

Authors: Magerl M, Germenis AE, Maas C, Maurer M

Abstract

A new form of hereditary angioedema (HAE) was identified in the year 2000. Its clinical appearance resembles HAE types I and II, which are caused by mutations that result in a deficiency of C1 inhibitor (C1-INH). In patients with the new form of HAE, C1-INH plasma levels and function values are normal, so it's termed HAE with normal C1-INH (HAE-nC1). HAE-nC1, in a subgroup of patients, is thought to be caused by mutations that affect the F12 gene. The diagnosis of HAE-nC1 is based on history and clinical criteria. There are no licensed drugs with proven treatment effects for HAE-nC1.

PMID: 28687110 [PubMed - in process]



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Burden of Illness and Quality-of-Life Measures in Angioedema Conditions.

Burden of Illness and Quality-of-Life Measures in Angioedema Conditions.:

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Burden of Illness and Quality-of-Life Measures in Angioedema Conditions.

Immunol Allergy Clin North Am. 2017 Aug;37(3):597-616

Authors: Caballero T, Prior N

Abstract

Burden of illness studies and evaluation of health-related quality of life using validated questionnaires have become an important task in the comprehensive management of angioedema conditions, mainly angioedema associated with chronic spontaneous urticaria and hereditary angioedema caused by C1-inhibitor deficiency. A review of the principal tools and studies is presented. Both diseases present a higher proportion of psychiatric disorders, impair work and studies productivity, and produce high direct and indirect costs. These assessments also have been useful to evaluate the positive impact of new drugs and interventions. More studies are desirable, especially in other types of angioedema disorders, such as hereditary angioedema with normal C1 inhibitor.

PMID: 28687112 [PubMed - in process]



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Pharmacoeconomics of Orphan Disease Treatment with a Focus on Hereditary Angioedema.

Pharmacoeconomics of Orphan Disease Treatment with a Focus on Hereditary Angioedema.:

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Pharmacoeconomics of Orphan Disease Treatment with a Focus on Hereditary Angioedema.

Immunol Allergy Clin North Am. 2017 Aug;37(3):617-628

Authors: Lumry WR

Abstract

This article discusses orphan diseases, their prevalence, legislative incentives to encourage development of therapies, and the impact of treatment on health care payment systems. Specifically, the cost burden of hereditary angioedema on patients, health care systems, and society is reviewed. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and overall burden of disease is explored. Changes in treatment paradigms to improve effect and reduce cost of treatment are presented.

PMID: 28687113 [PubMed - in process]



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Recent Advances in Adhesive Bonding: The Role of Biomolecules, Nanocompounds, and Bonding Strategies in Enhancing Resin Bonding to Dental Substrates

Recent Advances in Adhesive Bonding: The Role of Biomolecules, Nanocompounds, and Bonding Strategies in Enhancing Resin Bonding to Dental Substrates:

Abstract



Purpose of review

To present an overview on the main agents (i.e. biomolecules and nanocompounds) and/or strategies currently available to amplify or stabilize resin-dentin bonding.




Recent findings

According to studies retrieved for full-text reading (2014–2017), there are currently six major strategies available to overcome resin-dentin bond degradation: (1) use of collagen crosslinking agents, which may form stable covalent bonds with collagen fibrils, thus strengthening the hybrid layer; (2) use of antioxidants, which may allow further polymerization reactions over time; (3) use of protease inhibitors, which may inhibit or inactivate metalloproteinases; (4) modification of the bonding procedure, which may be performed by using the ethanol-wet bonding (EWB) technique or by applying an additional adhesive (hydrophobic) coating, thereby strengthening the hybrid layer; (5) laser treatment of the substrate prior to bonding, which may cause specific topographic changes in the surface of dental substrates, increasing bonding efficacy; and (6) reinforcement of the resin matrix with inorganic fillers and/or remineralizing agents, which may positively enhance physicomechanical properties of the hybrid layer.




Summary

With the present review, we contributed to the better understanding of adhesion concepts and mechanisms of resin-dentin bond degradation, showing the current prospects available to solve that problematic. In addition, adhesively-bonded restorations may be benefited by the use of some biomolecules, nanocompounds or alternative bonding strategies in order to minimize bond strength degradation.



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Use of Statins Is Associated with a Reduced Incidence of Oesophageal Adenocarcinoma

Systematic Review and Meta-analysis






Purpose

Laboratory studies have suggested that statins may have useful anti-cancer effects against Barrett's epithelial cancer lines. A variety of effects have been reported in clinical studies.




Methods

We performed a systematic review and meta-analysis of the association between statin use and the development of oesophageal cancer. Multiple databases were searched for studies reporting the association of statin use and oesophageal cancer. Meta-analysis on the relationship between statin use and cancer incidence was performed.




Results

Twenty publications met eligibility criteria, yielding 22 datasets for meta-analysis. All were observational studies. Population-level studies included 372,206 cancer cases and 6,086,906 controls. Studies examining adenocarcinoma development in Barrett's oesophagus included 1057 cancers and 17,741 controls. In patients with Barrett's oesophagus, statin use was associated with a reduced incidence of adenocarcinoma (pooled adjusted odds ratio (OR) 0.59 (95% confidence intervals 0.50–0.68)), with no heterogeneity between 11 studies. Population-based studies demonstrated more heterogeneity but showed that statin use was associated with a lower incidence of both oesophageal adenocarcinoma (OR 0.57 (0.43–0.76)) and all oesophageal cancers (OR 0.82 (0.7–0.88)). Information on statin type, dose, and duration was reported too infrequently for statistical analysis but individual studies showed a tendency to a dose- and duration-dependant decrease in cancer incidence.




Conclusions

Statin use is associated with a significantly lower incidence of oesophageal adenocarcinoma. This is seen in both Barrett's cohorts and general populations. Further studies should focus on drug, dose, and duration and the interaction with other risk and preventative factors.



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Young and advanced tumor—some 2D electrodynamic distinctions: melanoma and satellite during a vascular occlusion test: feasibility study

Young and advanced tumor—some 2D electrodynamic distinctions: melanoma and satellite during a vascular occlusion test: feasibility study:

Abstract

Conventional methods of electrobioimpedance imaging are not suited for adequate visualization of the skin electrical impedance landscape (SEL) because they do not provide high spatial resolution at large enough area of view. The skin electrodynamics introscopy (SEI) enabled dynamic spectral imaging of the SEL at 32 × 64 mm2 area with 1 mm spatial resolution. The focus of the study was to investigate the SEL distinguishing features between early and advanced-stage cancer at the model object of melanoma and its satellite. The analysis of the test-induced SEL metamorphoses was carried out at the periods of blood-stop and blood-restoration. It was found that the young tumor could be reliably visualized and distinguished by its antiphase hypoxia-induced response as compared to that of the advanced one. In response to the blood-restoration, an appearance of newly formed SEL clusters pointed out apparently at vascular abnormalities associated with the tumor. Similar SEL clusterization can be supposedly expected in response to any other test factors which affect cell permeability or/and blood viscosity. The proposed approach might be useful for more thorough mapping and staging malignancies.



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