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Background: Laryngeal dysfunction after thyroid and parathyroid surgery requires early recognition and a standardized approach for patients that present with voice, swallowing, and breathing issues. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to define the terms "immediate vocal fold paralysis" and "partial neural dysfunction" and to provide clinical consensus statements based on review of the literature, integrated with expert opinion of the group., Methods: A multidisciplinary expert panel constructed the manuscript and recommendations for laryngeal dysfunction after thyroid and parathyroid surgery. A meta-analysis was performed using the literature and published guidelines. Consensus was achieved using polling and a modified Delphi approach., Results: Twenty-two panelists achieved consensus on five statements regarding the role of early identification and standardization of evaluation for patients with "immediate vocal fold paralysis" and "partial neural dysfunction" after thyroid and parathyroid surgery., Conclusion: After endorsement by the AHNS Endocrine Section and Quality of Care Committee, it received final approval from the AHNS Council., (© 2020 Wiley Periodicals LLC.)

Purpose: Despite having a generally favorable prognosis, differentiated thyroid cancer is known to have a significant, long-term impact on the quality of life of survivors. We wished to investigate short- and long-term effects among thyroid cancer survivors following radioactive iodine therapy., Methods: We conducted eight focus groups (N = 47) to understand patients' experiences of short- and long-term effects after radioactive iodine treatment and the impact these treatment-related side effects had on patients' quality of life. We elicited responses regarding experiences with side effects following radioactive iodine treatment, particularly salivary, lacrimal, and nasal symptoms. We transcribed audiotapes and conducted qualitative analyses to identify codes and themes., Results: We identified eight broad themes from the qualitative analyses. Themes reflecting physical symptoms included dry mouth, salivary gland dysfunction, altered taste, eye symptoms such as tearing or dryness, and epistaxis. Psychosocial themes included lack of knowledge and preparation for treatment, regret of treatment, and distress that thyroid cancer is labeled as a "good cancer.", Conclusions: Thyroid cancer survivors reported a wide range of radioactive iodine treatment-related effects and psychosocial concerns that appear to reduce quality of life. The psychosocial concerns reported by participants underscore the significant unmet information and support needs prior to and following RAI treatment among individuals diagnosed with thyroid cancer., Implications for Cancer Survivors: Future research is needed to help both patients and physicians understand the effect of radioactive iodine on quality of life, and to better assess the benefits versus the risks of radioactive iodine therapy.

Objective: To survey a large cohort of thyroid cancer survivors from ThyCa on information needs and expectations of their treatment to better understand the pretreatment counseling, information, and support needs of this population., Methods: Anonymous survey of thyroid cancer survivors., Results: One thousand one hundred twenty-four patients with thyroid cancer participated in the survey. Three hundred sixty-two (37.44%) reported not having had a full understanding of their treatment plan and 407 (46.41%) reported that their thyroid cancer treatment did not conform to expectations. Patients diagnosed at younger ages were significantly more likely to report inadequate understanding of the treatment, failure of treatment to meet expectations, and call for greater attention to psychological well-being. Older patients were more likely to report unexpected effects on speech and swallowing. Regardless of age, patients most frequently called for greater attention to management of energy levels (endorsed by 61% of respondents), psychological well-being (50%), and weight changes (48%)., Conclusions: Improvements are needed in age-specific communication of thyroid cancer diagnosis and treatment., (© 2020 Wiley Periodicals, Inc.)

Background: Globally, the rapid growth of technology and its use as a development solution has generated much interest in digital health. In line with global trends, Bangladesh is also integrating technology into its health system to address disparities. Strong political endorsement and uptake of digital platforms by the government has influenced the rapid proliferation of such initiatives in the country. This paper aims to examine the implications of digital health on access to health care in Bangladesh, considering who uses electronic devices to access health information and services and why., Objective: This study aims to understand how access to health care and related information through electronic means (digital health) is affected by sociodemographic determinants (ie, age, gender, education, socioeconomic status, and personal and household ownership of mobile phones) in a semiurban community in Bangladesh., Methods: A cross-sectional survey of 854 households (between October 2013 and February 2014) and 20 focus group discussions (between February 2017 and March 2017) were conducted to understand (1) who owns electronic devices; (2) who, among the owners, uses these to access health information and services and why; (3) the awareness of electronic sources of health information; and (4) the role of intermediaries (family members or peers who helped to look for health information using electronic devices)., Results: A total of 90.3% (771/854) of households (471/854, 55.2% of respondents) owned electronic devices, mostly mobile phones. Among these, 7.2% (34/471) used them to access health information or services. Middle-aged (35-54 years), female, less (or not) educated, and poorer people used these devices the least (α=.05, α is the level of significance). The lack of awareness, discomfort, differences with regular care-seeking habits, lack of understanding and skills, and proximity to a health facility were the main reasons for not using devices to access digital health., Conclusions: Although influenced by sociodemographic traits, access to digital health is not merely related to device ownership and technical skill. Rather, it is a combination of general health literacy, phone ownership, material resources, and technical skill as well as social recognition of health needs and inequity. This study's findings should serve as a basis for better integrating technology within the health system and ensuring equitable access to health care., (©Tanvir Ahmed, Syed Jafar Raza Rizvi, Sabrina Rasheed, Mohammad Iqbal, Abbas Bhuiya, Hilary Standing, Gerald Bloom, Linda Waldman. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 21.07.2020.)

It is very exceptional that a new disease becomes a true pandemic. Since its emergence in Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, has spread to nearly all countries of the world in only a few months. However, in different countries, the COVID-19 epidemic takes variable shapes and forms in how it affects communities. Until now, the insights gained on COVID-19 have been largely dominated by the COVID-19 epidemics and the lockdowns in China, Europe and the USA. But this variety of global trajectories is little described, analysed or understood. In only a few months, an enormous amount of scientific evidence on SARS-CoV-2 and COVID-19 has been uncovered (knowns). But important knowledge gaps remain (unknowns). Learning from the variety of ways the COVID-19 epidemic is unfolding across the globe can potentially contribute to solving the COVID-19 puzzle. This paper tries to make sense of this variability-by exploring the important role that context plays in these different COVID-19 epidemics; by comparing COVID-19 epidemics with other respiratory diseases, including other coronaviruses that circulate continuously; and by highlighting the critical unknowns and uncertainties that remain. These unknowns and uncertainties require a deeper understanding of the variable trajectories of COVID-19. Unravelling them will be important for discerning potential future scenarios, such as the first wave in virgin territories still untouched by COVID-19 and for future waves elsewhere., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

China's engagement in global affairs has changed substantially in the 2010s. One aspect of the country's global reorientation has been its increased interest in, and willingness to play a role in, global health. In the early 2010s, the UK Department for International Development (DFID) initiated a collaboration with the Chinese government on a programme to support the country to play a greater and more effective global role in health and explore how the UK and China could work together on issues of key concern and contribute to improved global development outcomes. The programme worked with key Chinese agencies to carry out capacity building, support analysis of China's approaches to engagement in global health governance and assistance, and provide support to government decision making. It also trialled several small-scale interventions in third countries through which Chinese agencies gained experience of working on health programmes overseas. The article reports on the main findings of an evaluation commissioned by DFID to learn from the programme. The programme provided support at a key time in China's global reorientation; however, there is a need for continued development of capacity and systems for China to play the role envisaged by the country's leadership. There is also a need for continued exploration on the part of China and partners of how to effectively collaborate to support improved global outcomes., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Recent years have seen a rapid change in China's global engagement and a recognition that solving global challenges will need to take the changing role of China into account. The paper discusses China's growing involvement in global health. Health is an area where there is broad agreement over global priorities and, potentially, a fertile space to build new forms of collaboration that point the way towards the adaptation of global governance to a rapidly changing context., Results: Drawing on previous analyses of China's management of change in its domestic health reforms and interviews with a range of stakeholders in China, the UK and Switzerland, the paper argues that China's engagement in global health is developing and diversifying rapidly in response to the central government's desire to see a greater role for China in global health. This diversification is part of a pattern of change management familiar from China's domestic reform experience. Explorations underway by a range of Chinese agencies form part of a process of rapid experimentation and experiential learning that are informing China's search for (a) new global role(s)., Conclusions: China is undergoing rapid institutional innovation and developing capacity for greater global engagement, including in health; however, substantial, recent leadership commitments make clear Chinese agencies' need for continued exploration, innovation and rapid learning. How China engages globally is of significance to the world, not just China. The challenge for China, other global actors and multilateral organisations is to incorporate new approaches into existing global governance arrangements, including for the management of global health. This will require a willingness on all sides to learn from each other and invest the effort needed to build governance arrangements appropriate for the coming decades. This is not only important as a means of protecting global public health, but also as a demonstration of how governance arrangements can be adapted to the needs of a pluralistic global order in a context of rapid change.

The objective of this nationwide survey was to evaluate whether there has been a change in the practice regarding hospital release of differentiated thyroid cancer patients treated with 131 I since the publication of Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 addressing patient release. Methods: A survey was emailed to approximately 25,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc., and was available online from March to August 2018. Responses were included from adult patients regarding their most recent 131 I therapy received between 2011 and 2018 ("after 2011"). Responses to this survey were compared with those of a similar previous survey for 131 I therapies received between 1997 and 2009 ("before 2009"). Results: Of the 2,136 responses, 1,111 met the inclusion criteria. A similar percentage (∼98%) of patients were given oral or written radiation safety instructions (RSIs) after 2011 and before 2009, with a shift away from nuclear medicine physicians providing instructions after 2011 (43%) in comparison with before 2009 (54%; P < 0.001). More patients were able to discuss and individualize the RSIs after 2011 (67%) than before 2009 (29%; P < 0.001). However, 2% of patients do not recall ever receiving RSIs after 2011. After 2011, more patients were treated as outpatients (87%) than before 2009 (66%; P < 0.001). For outpatients, more patients were discharged within 30 min after receiving 131 I therapy after 2011 (78%) than before 2009 (72%; P = 0.002). The same percentage (0.6%) of patients traveled more than 2 h with at least 2 occupants in the vehicle within approximately 1 m of the patient after 2011 and before 2009. Immediately after therapy, a similar percentage of patients stayed in a nonprivate residence after 2011 (4%) and before 2009 (5%; P = 0.28). Of the 27 outpatients released within 30 min to nonprivate residences, 2 patients received 5.55-11.1 GBq (150-299 mCi) of 131 I. Conclusion: This survey suggests that since publication of the Nuclear Regulatory Commission Regulatory Issue Summary 2011-01 on patient release after radioiodine therapy, there have been improvements in some radiation safety practices on release of outpatients, as well as improvements in patient compliance on travel and lodging., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and do not have any conflicts of interest to declare.

Patients treated with 131 I may be identified at security checkpoints at various public facilities. The objective of this survey was to determine the frequency of detection, the spectrum of public facilities, the various methods of management of the situation by security agents, and the spectrum of physician documentation for patients regarding their 131 I therapy. Methods: Data were tabulated from a Thyroid Cancer Survivors' Association, Inc., survey emailed to approximately 15,000 associates and available online from December 2013 to December 2014. Responses were tabulated from respondents who reported that they were 18 y old or older, had received at least 1 131 I treatment for differentiated thyroid cancer, and were responding regarding their last 131 I treatment. Results: Of 621 respondents, 595 reported an attempt to pass through a public facility security checkpoint. Of these 595 patients, approximately 10% (57) were identified as being radioactive. The facility reported by 43 respondents was an airport for 35% (15), border crossing for 33% (14), government building for 19% (8), shopping mall for 7% (3), train station for 5% (2), and steel recycling plant for 2% (1). The security agent's management of the situation reported by 47 respondents included questioning for 81% (38), allowing them to proceed without a change in travel plans for 57% (27), requesting documentation of the therapy for 55% (26), rescanning for 55% (26), calling a member of the treating team for validation for 17% (8), "strip" searching for 4% (2), detaining such that a change in travel plans was required for 6% (3), and prohibiting continued travel for 4% (2). The period of detainment reported by these 47 respondents was less than 30 min for 57% (27), 30 to less than 60 min for 21% (10), 1 to less than 1.5 h for 15% (7), 1.5 to less than 2 h for 2% (1), 2-4 h for 0% (0), and greater than 4 h for 4% (2). Data regarding physician documentation are presented. Conclusion: The detection of radioactivity at a variety of security checkpoints at public facilities after 131 I therapy occurred in approximately 10% of respondents. Travel inconvenience is not infrequent and may require alteration of travel plans. Physicians should take steps to ensure that patients not only have appropriate documentation of their 131 I therapy with them but also have instructions regarding how security agents may verify their 131 I therapy., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

This article was drafted as part of a review of strategies for making progress toward universal health coverage in the countries of Asia and the Pacific. It focuses on strengthening the delivery of services, in the context of population aging. It argues that it is important to take into account big differences in development contexts and also the rapid, interconnected changes that many countries are experiencing. The article focuses especially on countries with relatively undeveloped institutions and pluralistic and highly segmented health sectors. It argues that attempts by these countries to import institutional arrangements from outside are likely to be complicated. It argues that government needs to focus on both short-term measures to meet immediate needs and the longer-term aim of establishing effective institutional arrangements. This means that they need to take into account the political factors that influence the direction of health system change. The article emphasizes the need to strengthen the capacity of the health system to address the growing challenge of chronic noncommunicable diseases to avoid heavy political pressure to expand hospital services. It then explores the opportunities and challenges associated with the rapid expansion of digital health services. It concludes with a discussion of government stewardship and management of health system transformation to address the major challenges associated with population aging.

Healthcare systems are increasingly recognised as complex, in which a range of non-linear and emergent behaviours occur. China's healthcare system is no exception. The hugeness of China, and the variation in conditions in different jurisdictions present very substantial challenges to reformers, and militate against adopting one-size-fits-all policy solutions. As a consequence, approaches to change management in China have frequently emphasised the importance of sub-national experimentation, innovation, and learning. Multiple mechanisms exist within the government structure to allow and encourage flexible implementation of policies, and tailoring of reforms to context. These limit the risk of large-scale policy failures and play a role in exploring new reform directions and potentially systemically-useful practices. They have helped in managing the huge transition that China has undergone from the 1970s onwards. China has historically made use of a number of mechanisms to encourage learning from innovative and emergent policy practices. Policy evaluation is increasingly becoming a tool used to probe emergent practices and inform iterative policy making/refining. This paper examines the case of a central policy research institute whose mandate includes evaluating reforms and providing feedback to the health ministry. Evaluation approaches being used are evolving as Chinese research agencies become increasingly professionalised, and in response to the increasing complexity of reforms. The paper argues that learning from widespread innovation and experimentation is challenging, but necessary for stewardship of large, and rapidly-changing systems.

Background: The Theory of Change (ToC) is a management and evaluation tool supporting critical thinking in the design, implementation and evaluation of development programmes. We document the experience of Future Health Systems (FHS) Consortium research teams in Bangladesh, India and Uganda with using ToC. We seek to understand how and why ToCs were applied and to clarify how they facilitate the implementation of iterative intervention designs and stakeholder engagement in health systems research and strengthening., Methods: This paper combines literature on ToC, with a summary of reflections by FHS research members on the motivation, development, revision and use of the ToC, as well as on the benefits and challenges of the process. We describe three FHS teams' experiences along four potential uses of ToCs, namely planning, communication, learning and accountability., Results: The three teams developed ToCs for planning and evaluation purposes as required for their initial plans for FHS in 2011 and revised them half-way through the project, based on assumptions informed by and adjusted through the teams' experiences during the previous 2 years of implementation. All teams found that the revised ToCs and their accompanying narratives recognised greater feedback among intervention components and among key stakeholders. The ToC development and revision fostered channels for both internal and external communication, among research team members and with key stakeholders, respectively. The process of revising the ToCs challenged the teams' initial assumptions based on new evidence and experience. In contrast, the ToCs were only minimally used for accountability purposes., Conclusions: The ToC development and revision process helped FHS research teams, and occasionally key local stakeholders, to reflect on and make their assumptions and mental models about their respective interventions explicit. Other projects using the ToC should allow time for revising and reflecting upon the ToCs, to recognise and document the adaptive nature of health systems, and to foster the time, space and flexibility that health systems strengthening programmes must have to learn from implementation and stakeholder engagement.

Background: Whether radioactive iodine ( 131 I) treatments for differentiated thyroid cancer should be performed as an outpatient or inpatient remains controversial. The objective of this study was to survey selected aspects of radiation safety of patients treated with 131 I for differentiated thyroid cancer as an outpatient., Methods: An e-mail invitation was sent to over 15,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. to complete a web-based survey on selected aspects of radiation safety regarding their last outpatient 131 I treatment., Results: A total of 1549 patients completed the survey. Forty-five percent (699/1541) of the respondents reported no discussion on the choice of an inpatient or outpatient treatment. Moreover, 5% (79/1541) of the respondents reported that their insurance company made the decision. Survey respondents recalled receiving oral and written radiation safety instructions 97% (1459/1504) and 93% (1351/1447) of the time, respectively. Nuclear medicine physicians delivered oral and written instructions to 54% (807/1504) and 41% (602/1462) of the respondents, respectively. Eighty-eight percent (1208/1370) of the respondents were discharged within 1 hour after receiving their 131 I treatment, and 97% (1334/1373) traveled in their own car after being released from the treating facility. Immediately post-therapy, 94% (1398/1488) of the respondents stayed at their own home or a relative's home, while 5% (76/1488) resided in a public lodging. The specific recommendations received by patients about radiation precautions varied widely among the respondents. Ninety-nine percent (1451/1467) of the respondents believed they were compliant with the instructions., Conclusion: This is the largest, patient-based survey published regarding selected radiation safety aspects of outpatient 131 I treatment. This survey suggests several concerns about radiation safety, such as the decision process regarding inpatient versus outpatient treatment, instructions about radiation safety, transportation, and lodging after radioiodine therapy. These concerns warrant further discussion, guidelines, and/or policies.

The WHO launched a Global Action Plan on antimicrobial resistance (AMR) in 2015. World leaders in the G7, G20 and the UN General Assembly have declared AMR to be a global crisis. World leaders have also adopted universal health coverage (UHC) as a key target under the sustainable development goals. This paper argues that neither initiative is likely to succeed in isolation from the other and that the policy goals should be to both provide access to appropriate antimicrobial treatment and reduce the risk of the emergence and spread of resistance by taking a systems approach. It focuses on outpatient treatment of human infections and identifies a number of interventions that would be needed to achieve these policy goals. It then shows how a strategy for achieving key attributes of a health system for UHC can take into account the need to address AMR as part of a UHC strategy in any country. It concludes with a list of recommended priority actions for integrating initiatives on AMR and UHC., Competing Interests: Competing interests: None declared.

The aim of this paper is to contribute to debates about how governments and other stakeholders can influence the application of ICTs to increase access to safe, effective and affordable treatment of common illnesses, especially by the poor. First, it argues that the health sector is best conceptualized as a 'knowledge economy'. This supports a broadened view of health service provision that includes formal and informal arrangements for the provision of medical advice and drugs. This is particularly important in countries with a pluralistic health system, with relatively underdeveloped institutional arrangements. It then argues that reframing the health sector as a knowledge economy allows us to circumvent the blind spots associated with donor-driven ICT-interventions and consider more broadly the forces that are driving e-health innovations. It draws on small case studies in Bangladesh and China to illustrate new types of organization and new kinds of relationship between organizations that are emerging. It argues that several factors have impeded the rapid diffusion of ICT innovations at scale including: the limited capacity of innovations to meet health service needs, the time it takes to build new kinds of partnership between public and private actors and participants in the health and communications sectors and the lack of a supportive regulatory environment. It emphasises the need to understand the political economy of the digital health knowledge economy and the new regulatory challenges likely to emerge. It concludes that governments will need to play a more active role to facilitate the diffusion of beneficial ICT innovations at scale and ensure that the overall pattern of health system development meets the needs of the population, including the poor.

A recent editorial by Naoki Ikegami has proposed three key lessons from Japan's experience of achieving virtually universal coverage with primary healthcare services: the need to integrate the existing providers of primary healthcare services into the organised health system; the need to limit government commitments to finance hospital services and the need to empower providers of primary healthcare to influence decisions that influence their livelihoods. Although the context of low- and middle-income countries (LMICs) differs in many ways from Japan in the late 19th and early 20th centuries, the lesson that short-term initiatives to achieve universal coverage need to be complemented by an understanding of the factors influencing long-term change management remains highly relevant., (© 2017 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

This paper discusses health policy and systems research in complex and rapidly changing contexts. It focuses on ethical issues at stake for researchers working with government policy makers to provide evidence to inform major health systems change at scale, particularly when the dynamic nature of the context and ongoing challenges to the health system can result in unpredictable outcomes. We focus on situations where 'country ownership' of HSR is relatively well established and where there is significant involvement of local researchers and close ties and relationships with policy makers are often present. We frame our discussion around two country case studies with which we are familiar, namely China and South Africa and discuss the implications for conducting 'embedded' research. We suggest that reflexivity is an important concept for health system researchers who need to think carefully about positionality and their normative stance and to use such reflection to ensure that they can negotiate to retain autonomy, whilst also contributing evidence for health system change. A research process informed by the notion of reflexive practice and iterative learning will require a longitudinal review at key points in the research timeline. Such review should include the convening of a deliberative process and should involve a range of stakeholders, including those most likely to be affected by the intended and unintended consequences of change., (© 2016 The Authors Developing World Bioethics Published by John Wiley & Sons Ltd.)

The emergence and spread of antibiotic resistant pathogens poses a big challenge to policy-makers, who need to oversee the transformation of health systems that evolved to provide easy access to these drugs into ones that encourage appropriate use of antimicrobials, whilst reducing the risk of resistance. This is a particular challenge for low and middle-income countries with pluralistic health systems where antibiotics are available in a number of different markets. This review paper considers access and use of antibiotics in these countries from a complex adaptive system perspective. It highlights the main areas of intervention that could provide the key to addressing the sustainable long term use and availability of antibiotics. A focus on the synergies between interventions addressing access strategies, antibiotic quality, diagnostics for low-resource settings, measures to encourage just and sustainable decision making and help seeking optimal therapeutic and dosing strategies are key levers for the sustainable future of antibiotic use. Successful integration of such strategies will be dependent on effective governance mechanisms, effective partnerships and coalition building and accurate evaluation systems at national, regional and global levels.

The effectiveness of antibiotics in treating bacterial infections is decreasing in China because of the widespread development of resistant organisms. Although China has enacted a number of regulations to address this problem, but the impact is very limited. This paper investigates the implementation of these regulations through the lens of complex adaptive systems (CAS). It presents the findings from reviews of relevant policy documents and published papers. The paper identifies different types of agent and explores their interaction with regard to the use of antibiotics and their responses to changes of the regulations. It focuses particularly on the impact of perverse financial incentives on overall patterns of use of antibiotics. Implications for the possibilities of nonlinear results, interactive relationships, and new pathways of policy implementation are discussed. The paper concludes that policy-makers need to better understand the objectives, incentives and potential adaptive behaviors of the agents when they implement interventions to improve antibiotic use and reduce the risk of emergence of resistant organisms.

Purpose: We previously found that an epithelial-to-mesenchymal transition (EMT)-based gene expression signature was highly correlated with the first principal component (PC1) of 326 colorectal cancer tumors and was prognostic. This study was designed to improve these signatures for better prediction of metastasis and outcome., Experimental Design: A total of 468 colorectal cancer tumors including all stages (I-IV) and metastatic lesions were used to develop a new prognostic score (ΔPC1.EMT) by subtracting the EMT signature score from its correlated PC1 signature score. The score was validated on six other independent datasets with a total of 3,697 tumors., Results: ΔPC1.EMT was found to be far more predictive of metastasis and outcome than its parent scores. It performed well in stages I to III, among microsatellite instability subtypes, and across multiple mutation-based subclasses, demonstrating a refined capacity to predict distant metastatic potential even in tumors with a "good" prognosis. For example, in the PETACC-3 clinical trial dataset, it predicted worse overall survival in an adjusted multivariable model for stage III patients (HR standardized by interquartile range [IQR] = 1.50; 95% confidence interval, 1.25-1.81; P = 0.000016, N = 644). The improved performance of ΔPC1.EMT was related to its propensity to identify epithelial-like subpopulations as well as mesenchymal-like subpopulations. Biologically, the signature was correlated positively with RAS signaling but negatively with mitochondrial metabolism. ΔPC1.EMT was a "best of assessed" prognostic score when compared with 10 other known prognostic signatures., Conclusions: The study developed a prognostic signature score with a propensity to detect non-EMT features, including epithelial cancer stem cell-related properties, thereby improving its potential to predict metastasis and poorer outcome in stage I-III patients., (©2015 American Association for Cancer Research.)

This paper presents a conceptual approach for discussing health information seeking among poor households in Africa and Asia. This approach is part of a larger research endeavor aimed at understanding how health systems are adapting; with possibilities and constraints emerging. These health systems can be found in a context of the changing relationships between states, markets and civil society in low and middle income countries. The paper starts from an understanding of the health sector as a "health knowledge economy", organized to provide people with access to knowledge and advice. The use of the term "health knowledge economy" draws attention to the ways the health sector is part of a broader knowledge economy changing the way individuals and households obtain and use specialist information. The paper integrates an actor centric approach with the theory of planned behavior. It seeks to identify the actors engaged in the health knowledge economy as a precursor to longer term studies on the uptake of innovations integrating health services with mobile phones, commonly designated as mHealth, contributing to an understanding of the potential vulnerabilities of poor people, and highlighting possible dangers if providers of health information and advice are strongly influenced by interest groups.

Background: This paper explores the evolution of schemes for rural finance in China as a case study of the long and complex process of health system development. It argues that the evolution of these schemes has been the outcome of the response of a large number of agents to a rapidly changing context and of efforts by the government to influence this adaptation process and achieve public health goals., Methods: The study draws on several sources of data including a review of official policy documents and academic papers and in-depth interviews with key policy actors at national level and at a sample of localities., Results: The study identifies three major transition points associated with changes in broad development strategy and demonstrates how the adaptation of large numbers of actors to these contextual changes had a major impact on the performance of the health system. Further, it documents how the Ministry of Health viewed its role as both an advocate for the interests of health facilities and health workers and as the agency responsible for ensuring that government health system objectives were met. It is argued that a major reason for the resilience of the health system and its ability to adapt to rapid economic and institutional change was the ability of the Ministry to provide overall strategy leadership. Additionally, it postulates that a number of interest groups have emerged, which now also seek to influence the pathway of health system development., Conclusions: This history illustrates the complex and political nature of the management of health system development and reform. The paper concludes that governments will need to increase their capacity to analyze the health sector as a complex system and to manage change processes.

Rural households in India rely extensively on informal biomedical providers, who lack valid medical qualifications. Their numbers far exceed those of formal providers. Our study reports on the education, knowledge, practices and relationships of informal providers (IPs) in two very different districts: Tehri Garhwal in Uttarakhand (north) and Guntur in Andhra Pradesh (south). We mapped and interviewed IPs in all nine blocks of Tehri and in nine out of 57 blocks in Guntur, and then interviewed a smaller sample in depth (90 IPs in Tehri, 100 in Guntur) about market practices, relationships with the formal sector, and their knowledge of protocol-based management of fever, diarrhoea and respiratory conditions. We evaluated IPs' performance by observing their interactions with three patients per condition; nine patients per provider. IPs in the two districts had very different educational backgrounds-more years of schooling followed by various informal diplomas in Tehri and more apprenticeships in Guntur, yet their knowledge of management of the three conditions was similar and reasonably high (71% Tehri and 73% Guntur). IPs in Tehri were mostly clinic-based and dispensed a blend of allopathic and indigenous drugs. IPs in Guntur mostly provided door-to-door services and prescribed and dispensed mainly allopathic drugs. In Guntur, formal private doctors were important referral providers (with commissions) and source of new knowledge for IPs. At both sites, IPs prescribed inappropriate drugs, but the use of injections and antibiotics was higher in Guntur. Guntur IPs were well organized in state and block level associations that had successfully lobbied for a state government registration and training for themselves. We find that IPs are firmly established in rural India but their role has grown and evolved differently in different market settings. Interventions need to be tailored differently keeping in view these unique features., (Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. © The Author(s) 2014; all rights reserved.)

The rapid evolution and spread of health markets across low and middle-income countries (LMICs) has contributed to a significant increase in the availability of health-related goods and services around the world. The support institutions needed to regulate these markets have lagged behind, with regulatory systems that are weak and under-resourced. This paper explores the key issues associated with regulation of health markets in LMICs, and the different goals of regulation, namely quality and safety of care, value for money, social agreement over fair access and financing, and accountability. Licensing, price controls, and other traditional approaches to the regulation of markets for health products and services have played an important role, but they have been of questionable effectiveness in ensuring safety and efficacy at the point of the user in LMICs. The paper proposes a health market systems conceptual framework, using the value chain for the production, distribution and retail of health goods and services, to examine regulation of health markets in the LMIC context. We conclude by exploring the changing context going forwards, laying out implications for future heath market regulation. We argue that the case for new approaches to the regulation of markets for health products and services in LMICs is compelling. Although traditional "command and control" approaches will have a place in the toolkit of regulators, a broader bundle of approaches is needed that is adapted to the national and market-level context of particular LMICs. The implication is that it is not possible to apply standard or single interventions across countries, as approaches proven to work well in one context will not necessarily work well elsewhere.

Background: Alpha-fetoprotein (AFP)-secreting hepatocellular carcinomas (HCC) represent a genetically distinct subset of tumors often associated with a worse prognosis. However, the molecular mechanisms that underlie these phenotypic differences remain poorly understood., Methods: HCC tumor samples from 27 patients were profiled using the Affymetrix 133 Plus 2.0 GeneChips. GeneGO Metacore software was used to identify altered biologic pathways. Expression validation was confirmed by RT-PCR. Manipulation of miR-675 by overexpression and antagomir-mediated knockdown was carried out with subsequent evaluation of effects on cell behavior by cell cycle, proliferation, invasion, and growth in soft agar assays., Results: We identified a strong relationship between primary tumor H19 gene expression and elevated serum AFP. H19 has recently been identified to encode microRNA-675 (miR-675), and we confirmed the relationship in an independent sample of patients. Pathway analyses of the effect of miR-675 overexpression in hepatoma cells revealed a predominant upregulation of cell adhesion and cell cycle initiation pathways. We have demonstrated that miR-675 mediates increases in proliferation and an accumulation of cells with tetraploid DNA content associated with a repression of Rb. We also demonstrated that overexpression of miR-675 alters cellular morphology, reduces invasive potential, and increases anchorage-independent growth capacity. These findings are consistent with a mesenchymal-to-epithelial transition, associated with a reduction in the expression of the key EMT mediator, Twist1., Conclusions: Expression of the miR-675 in hepatocellular carcinoma links a dramatic upregulation of proliferative and growth capacity with inhibition of motility in HCC cells.

Many Asian countries are in the midst of multiple interconnected social, economic, demographic, technological, institutional and environmental transitions. These changes are having important impacts on health and well-being and on the capacity of health systems to respond to health-related problems. This paper focuses on the creation of institutions to overcome information asymmetry and encourage the provision of safe, effective and affordable health services in this context of complexity and rapid change. It presents a review of literature on different approaches to the analysis of the management of system development and institution-building. There is a general agreement that the outcome of an intervention depends a great deal on the way that a large number of agents respond. Their response is influenced by the institutional arrangements that mediate relationships between health sector actors and also by their understandings and expectations of how other actors will respond. The impact of a policy or specific intervention is difficult to predict and there is a substantial risk of unintended outcomes. This creates the need for an iterative learning approach in which widespread experimentation is encouraged, good and bad experiences are evaluated and policies are formulated on the basis of the lessons learned. This enables actors to learn their roles and responsibilities and the appropriate responses to new incentive structures. The paper concludes with an outline of the information needs of managers of health system change in societies in the midst of rapid development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Cytopenias occur frequently in systemic lupus erythematosus, rheumatoid arthritis, Felty's syndrome, and large granular lymphocyte (LGL) leukemia, but the bone marrow microenvironment has not been systematically studied. In LGL leukemia (n = 24), retrospective analysis of bone marrow (BM) histopathology revealed severe fibrosis in 15 of 24 patients (63%) in association with the presence of cytopenias, occurrence of autoimmune diseases, and splenomegaly, but was undetectable in control cases with B cell malignancies (n = 11). Fibrosis severity correlated with T cell LGL cell numbers in the BM, but not in the periphery, suggesting deregulation is limited to the BM microenvironment. To identify fibrosis-initiating populations, primary mesenchymal stromal cultures (MSCs) from patients were characterized and found to display proliferation kinetics and overabundant collagen deposition, but displayed normal telomere lengths and osteoblastogenic, chondrogenic, and adipogenic differentiation potentials. To determine the effect of fibrosis on healthy hematopoietic progenitor cells (HPCs), bioartificial matrixes from rat tail or purified human collagen were found to suppress HPC differentiation and proliferation. The ability of patient MSCs to support healthy HSC proliferation was significantly impaired, but could be rescued with collagenase pretreatment. Clustering analysis confirmed the undifferentiated state of patient MSCs, and pathway analysis revealed an inverse relationship between cell division and profibrotic ontologies associated with reduced basic fibroblast growth factor production, which was confirmed by ELISA. Reconstitution with exogenous basic fibroblast growth factor normalized patient MSC proliferation, collagen deposition, and HPC supportive function, suggesting LGL BM infiltration and secondary accumulation of MSC-derived collagen is responsible for hematopoietic failure in autoimmune-associated cytopenias in LGL leukemia.

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Objectives: To determine the frequency and consequences of patient-reported post-thyroidectomy voice disorder (PTVD) after surgery for thyroid cancer., Study Design: Retrospective review of data gathered from a survey., Participants: Members of the Thyroid Cancer Survivors' Association (ThyCa)., Methods: ThyCa members were asked about their thyroid disease and surgery, voice disturbance, impact on quality of life, treatment, and non-identifying demographics in a 36-item electronic questionnaire. Patients with preoperative voice disturbance or vocal fold immobility and those reporting postoperative vocal fold paralysis were excluded., Results: A total of 4426 members responded (37% response rate), and PTVD was reported by 51.1% of responders. Most were temporary (85.9%), with a minority reporting permanent hoarseness. Rates of postoperative dysphonia were similar between the extent of surgery and histology. Patients with PTVD predominantly characterized their impairment as loss of loudness and an inability to shout or sing. Nearly a quarter of patients reporting PTVD identified detrimental impact to their professional or personal lives. Only 57 patients (3.4%) were offered voice therapy; however, more than two-thirds of them (73.7%) experienced at least partial improvement., Conclusions: We report the results of a large-scale patient survey to underscore the commonness of postoperative hoarseness and its impact on patients., Level of Evidence: 4., (Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Although considerable progress has been made toward understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We conducted global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low- and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term energetic, anabolic, and phospholipid catabolism with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy., (©2012 AACR.)

SIRT1 is a NAD(+)-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Importantly, immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA double-strand break repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA double-strand break. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and regulates hMOF and TIP60 through deacetylation and provide additional mechanistic insights by which SIRT1 regulates DNA damage response.

With traditional 2-color Förster Resonance Energy Transfer (FRET) microscopy, valuable quantitative analyses can be conducted. Correlations of donor (D), acceptor (A) and their ratios (D:A) with energy transfer efficiency (E%) or distance (r) allows measurement of changes between control and experimental samples; also, clustered vs. random assembly of cellular components can be differentiated. Essentially, only the above three parameters D, A and D:A vs. E% are the basis for these deductions. 3-color FRET uses the same basic parameters, but exponentially expands the opportunities to quantify interrelationships among 3 cellular components. We investigated a number of questions based on the results of a triple combination (F1-F2-F3) of TFP-NWASP/Venus-IQGAP1/mCherry-Actin - all involved in the nucleation of actin - to apply the extensive analysis assay possible with 3-color FRET. How do changing N-WASP or IQGAP1 fluorescence levels affect actin fluorescence? What is the effect on E% of NWASP-actin by IQGAP1 or E% of IQGAP1-actin by N-WASP? These and other questions are explored in the context of all proteins of interest being in FRET distance vs. any two in the absence of the third. 4 cases are compared based on bleed-through corrected FRET: (1) all 3 interact, (2) only F1-F3 and F2-F3 [not F1-F2], (3) only F1-F2 and F2-F3 interact [not F1-F3], (4) only F1-F2 and F1-F3 interact [not F2-F3]. Other than describing the methodology in detail, several biologically relevant results are presented showing how E% (i.e. distance), fluorescence levels and ratios are affected in each of the cases. These correlations can only be observed in a 3-fluorophore combination. 3-color FRET will greatly expand the investigative range of quantitative analysis for the life-science researcher.

An external cavity using a binary phase grating has been developed to achieve coherent combining of five quantum-cascade lasers emitting at 4.65 μm. The grating phase profile is designed to combine five beams of equal intensities into a single beam with a good efficiency (~75%). The performances of this cavity concerning output power, stability, combining efficiency and beam quality are detailed. We report a CW combining efficiency of 66% corresponding to an output power of ~0.5 W with a good beam quality (M(2)<1.6)., (© 2011 Optical Society of America)

There has been a dramatic spread of market relationships in many low- and middle-income countries. This spread has been much faster than the development of the institutional arrangements to influence the performance of health service providers. In many countries poor people obtain a large proportion of their outpatient medical care and drugs from informal providers working outside a regulatory framework, with deleterious consequences in terms of the safety and efficacy of treatment and its cost. Interventions that focus only on improving the knowledge of these providers have had limited impact. There is a considerable amount of experience in other sectors with interventions for improving the performance of markets that poor people use. This paper applies lessons from this experience to the issue of informal providers, drawing on the findings of studies in Bangladesh and Nigeria. These studies analyse the markets for informal health care services in terms of the sources of health-related knowledge for the providers, the livelihood strategies of these providers and the institutional arrangements within which they build and maintain their reputation. The paper concludes that there is a need to build a systematic understanding of these markets to support collaboration between key actors in building institutional arrangements that provide incentives for better performance.

Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82-0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.

This paper is concerned with the management of health system changes aimed at substantially increasing the access to safe and effective health services. It argues that an effective health sector relies on trust-based relationships between users, providers and funders of health services, and that one of the major challenges governments face is to construct institutional arrangements within which these relationships can be embedded. It presents the case of China, which is implementing an ambitious health reform, drawing on a series of visits to rural counties by the author over a 10-year period. It illustrates how the development of reform strategies has been a response both to the challenges arising from the transition to a market economy and the result of actions by different actors, which have led to the gradual creation of increasingly complex institutions. The overall direction of change has been strongly influenced by the efforts made by the political leadership to manage a transition to a modern economy which provides at least some basic benefits to all. The paper concludes that the key lessons for other countries from China's experience with health system reform are less about the detailed design of specific interventions than about its approach to the management of institution-building in a context of complexity and rapid change., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Although a number of intermediate transport initiatives have been used in some developing countries, available evidence reveals a dearth of local knowledge on the effect of these rural informal transport mechanisms on access to maternal health care services, the cost of implementing such schemes and their scalability. This paper, attempts to provide insights into the functioning of the informal transport markets in facilitating access to maternal health care. It also demonstrates the role that higher institutions of learning can play in designing projects that can increase the utilization of maternal health services., Objectives: To explore the use of intermediate transport mechanisms to improve access to maternal health services, with emphasis on the benefits and unintended consequences of the transport scheme, as well as challenges in the implementation of the scheme., Methods: This paper is based on the pilot phase to inform a quasi experimental study aimed at increasing access to maternal health services using demand and supply side incentives. The data collection for this paper included qualitative and quantitative methods that included focus group interviews, review of project documents and facility level data., Results: There was a marked increase in attendance of antenatal, and delivery care services, with the contracted transporters playing a leading role in mobilizing mothers to attend services. The project also had economic spill-over effects to the transport providers, their families and community generally. However, some challenges were faced including difficulty in setting prices for paying transporters, and poor enforcement of existing traffic regulations., Conclusions and Implications: The findings indicate that locally existing resources such as motorcycle riders, also known as "boda boda" can be used innovatively to reduce challenges caused by geographical inaccessibility and a poor transport network with resultant increases in the utilization of maternal health services. However, care must be taken to mobilize the resources needed and to ensure that there is enforcement of laws that will ensure the safety of clients and the transport providers themselves.

We have designed a high-efficiency array generator composed of subwavelength grooves etched in a GaAs substrate for operation at 4.5 μm. The method used combines rigorous coupled wave analysis with an optimization algorithm. The optimized beam splitter has both a high efficiency (∼96%) and a good intensity uniformity (∼0.2%). The fabrication error tolerances are numerically calculated, and it is shown that this subwavelength array generator could be fabricated with current electron beam writers and inductively coupled plasma etching. Finally, we studied the effect of a simple and realistic antireflection coating on the performance of the beam splitter.

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin.

Identification of the site of origin for 'malignancy with unknown primary' remains a challenge for modern pathology. Correct diagnosis is critical to defining the most beneficial treatment for the patient. Standard pathological approaches combine morphology and immunohistochemical (IHC) studies to first subclassify cytokeratin-positive carcinomas into adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, and urothelial carcinoma. Subsequently, organ-specific IHC-markers, if available, are used to assign the tumor's primary site of origin. Previous gene expression classifiers have shown promise in tumor classification but cannot readily be integrated into standard practice because they ignore the algorithmic hierarchy used by pathologists. Here we present a novel hybrid approach integrating a hierarchy of gene expression classifiers into the algorithmic method used with IHC. In this method, a tumor is initially assigned to one of the carcinoma subclasses by the top tier classifier. Dependent on initial classification, one of three second-tier classifiers assign primary site resulting in both carcinoma subtype and primary site classification. First tier classifier accuracies were 89%, 88%, and 75% for cross-validation, independent, and institutional independent test sets, respectively. Second tier accuracies were 87%, 90%, and 87% for adenocarcinoma, squamous, and neuroendocrine carcinoma respectively. Therefore, we can successfully separate the four main subtypes of carcinoma and subsequently assign primary site by incorporation of gene expression-based classifiers into the standard algorithmic pathology approach.