India accounts for the highest number of maternal and child deaths globally. A large body of empirical research suggests that improvement in the coverage of institutional delivery is essential to reduce the burden of maternal and child death. However the dynamics of choice of place of delivery is poorly understood. Using qualitative survey data consisting of twelve focus group discussions, conducted in a rural setting of West Bengal, India, this study aims to understand the reasons behind preferring home or institution for delivery. Findings reveal that some women who underwent an institutional delivery preferred to deliver their baby at home. On the other hand, of women who delivered their baby at home, 60% wanted to deliver their babies in institutions but could not do so, primarily due to the unwillingness of family members and misreporting of the onset of true labour pain. With the help of Accredited Social Health Activists, the village level health workers, there is need for an intervention that focuses on educating household members  about birth preparedness, and identification of true labour pain. Janani Suraksha Yojana (JSY) in April 2005 to encourage women of low socioeconomic status to give birth in health facilities [India accounts for the highest number of maternal 45000 in 2015) [015 [2] gcilities , 4. Accocilities , the fedA host of factors are linked with the utilization of institutions for delivery. Thaddeus and Maine  grouped predisposing factors such as age, gender, marital status, family size, social status, education and race;enabling factors such as family income, health insurance, service availability and health level/symptoms or perceived sickness; andthe need to use available services, which perhaps is the most powerful predictor of healthcare utilization. The need is defined in two categories–perceived need and evaluative need. Perceived need is defined as “how people view their own general health and functional state, as well as how they experience symptoms of illness, pain, and worries about their health and whether or not they judge their problems to be of sufficient importance and magnitude to seek professional help. “Evaluative need refers to a decision based on previous diagnoses, co-morbidity burden, evaluated illness severity and other conditions which have already been evaluated” .In addition, many empirical studies have documented the socioeconomic, demographic, program and policy related determinants of institutional delivery –14. MostMost public datasets available for use  gather iAgainst this knowledge gap, a qualitative survey was conducted in a rural setting of the West Bengal, India, to explore answers of two questions: i) why some women delivered the baby in an institution, which is crucial for maternal and child survival, and ii) why some women delivered the baby at home, which increases the incidence of maternal and child deaths. A qualitative survey approach was deemed suitable for this investigation as the literature on this issue requires further exploration and the discussion around this topic is usually unnoticed in standardized quantitative survey approaches.This study was conducted with the Birbhum Population Project (BIRPOP) of the Society for Health and Demographic Surveillance (SHDS), a Health and Demographic Surveillance System (HDSS) located in Birbhum district, West Bengal, India . A predoThis study adopted a qualitative survey research approach, consisting of a purposively selected sample of 111 women for 12 focus group discussions (FGDs) to understand preference of place of delivery among women. This qualitative study design has followed the guidance of the Consolidated Criteria for Reporting Qualitative Studies (COREQ) recommended for reporting studies that use interviews and FGDs . COREQ iThe survey was conducted in the month of November , in all four administrative blocks of HDSS-BIRPOP accounting for three FGDs in each block. Out of twelve FGDs, three FGDs comprised eight women in each group, four FGDs comprised nine women in each group, four FGDs comprised 10 women in each group, and one FGD comprised 11 women. While making group composition, an attempt was made to ensure representation of at least one member from all religious and social groups to avoid any biased discussion. An attempt was made to ensure that both, women who had institutional deliveries and those who delivered at home, participated in the discussion. The select researchers from HDSS-BIRPOP participated to moderate and facilitate the FGDs. The resource persons (designated as “surveyor”) who had a minimum of an undergraduate degree with previous experience moderating FGDs were selected and trained to conduct the interviews, and a standardized audio recording device  was used to record the interviews. The field monitoring team consisted of two persons  who were appointed to monitor the FGD protocol. Moderators invited consenting participants and introduced themselves before starting the FGDs. The surveyors explained the purpose of the HDSS-BIRPOP and discussion strategy to the participants in the FGD. A guiding questionnaire used for FGDs is available in the supplementary document .Santhali language, as required. Upon obtaining an informed and written consent from the survey participants, the FGDs were conducted. Upon finishing 12 FGDs, the survey information was deemed sufficient as moderators noticed the replication in response [In FGDs, the first step of query was to understand whether the place of delivery of a woman’s recent child (within three years preceding the survey date) was in keeping with her choice. If the response was affirmative, further questions were posed to understand the reasons, and if the answer was negative, they were asked to substantiate their preference for place of delivery and the reasons for it. The interview was conducted in the Bengali or response .According to the World Health Organization, “a skilled attendant is an accredited health professional—such as a midwife, doctor or nurse—who has been educated and trained to proficiency in the skills needed to manage normal (uncomplicated) pregnancies, childbirth and the immediate postnatal period, and in the identification, management and referral of complications in women and newborns”. Thus, aSanthali, having at least an undergraduate training (where English language was the medium of instruction and education), translated the responses to English. In the second stage, another set of researchers with a similar educational background randomly checked nearly 60% of the translated FGDs. The accuracy of the transcribed responses was verified and approved for research by the HDSS-BIRPOP Ethics Review Board. An excel database spreadsheet was developed to code the response of different categories  attached to the participant’s unique identification number. The title and sub-title were assigned against the response. After all the comments on preference for place of delivery were coded, the common categories of the responses were sorted. The findings were summarized for each subcategory, noting similarities and differences across groups. The powerful quotes (translated verbatim) from each sub-section were added. Apart from Microsoft Excel [The verbatim responses obtained from the focus group discussions (FGDs) were translated into English. To nullify the effect of intra-observer and inter-observer reproducibility, two level translation processes were opted. In the first stage, two HDSS-BIRPOP researchers who were native speakers of Bengali or ft Excel  used to ft Excel  was usedEthical approval was obtained from the ethics review committee appointed by the Chairperson of the governing body of HDSS-BIRPOP. Only upon obtaining an informed and written consent from the participants they were enrolled in an FGD. To reiterate, the study adhered to COREQ guidelines devised for qualitative study.A total 55 of the interviewed women  reported that they delivered their last child in an institution. Among the eighteen tribal women who reported institutional deliveries, four women (22%) primarily wanted to deliver their baby at home, but upon experiencing some problems they opted to go to an institution. A 25 year old tribal mother of three children, with eight years of education, preferred to deliver at home but ended up going to an institution. She explained the reason behind her decision:I waited at home for delivery, but when it was not taking place even after spending a long time, I did not take any further risk and rushed to the nearby nursing home.”“Concurring with Aday and Andersen’s model of healthcare-seeking behaviour, the deteriorating health condition due to pregnancy (perceived need) led her to choose an institutional delivery . Studies on nationally representative surveys have indicated that Scheduled Tribe women are less likely to have an institutional delivery compared to women of other social groups . The SchI was afraid of going to the hospital, I had a language problem.”“Anganwadi Worker (AWW) about the importance of an institutional delivery were inclined to opt for a health facility for their delivery. The ASHA, a village level health worker appointed under the National Health Mission to spread awareness about health and its social determinants, can mobilize the community towards local health planning, increased utilization and accountability of existing health services [Thus the spatial disadvantage combined with social (such as language) and economic seclusion could be reasons for the relative reluctance for institutional delivery, although they ended up delivering at the facility. A recent metareview  identifiservices .All 55 women who opted for institutional delivery had a common denominator–they were all exposed to antenatal care (ANC) checkups administered by ASHAs, and/or they were educated by the ASHA, AWW, or their neighbours. Keeping in mind the alarmingly high maternal and child mortality in India and other developing countries, national and international public health leaders and professionals have proposed a comprehensive strategy to improve the continuum of reproductive, maternal, newborn and child health (RMNCH) care . In thisI delivered at the hospital because if any problem occurs, the doctors can manage, which is not possible at home”.“Although the woman had a very low level of education, through the IEC done by the ASHA, she learned the downsides of a home delivery. Community level health workers like an ASHA or AWW play a crucial role in communicating the benefits of institutional delivery in India, and the same is true for other low and middle income countries. For example, in Ethiopia the Health Extension Workers are key to promoting institutional delivery for every women and have succeeded tremendously .A total of 55 women selected for the study delivered their baby at home. However, it is surprising to note that 33 of the 55 women (that is 60%) preferred to deliver their baby at the health facility, but they could not do so due to various reasons. Out of 33, eight women replied that the unwillingness of family members to take them to institutions led to home delivery although they all wanted to go to the health facility for delivery. A 20-year-old tribal woman with twelve years of education said:My parents-in-law were reluctant to take me to the hospital. So I was forced to stay at home. I wanted to go to the hospital but it did not happen.”“within five minutes of delivery”. Non-involvement of family members, especially the husband in reproductive health behavior is well-documented [The woman also regrets that because of the home delivery her first child died “cumented . Most wocumented . Thus, ecumented ,32. Althcumented . ConsequA husband’s role in maternal care is said to be crucial in maternal healthcare behaviour. Especially in rural settings in India, a patriarchal society restricts women’s decision-making power . The tenMy husband was absent at that time. So I did not go to the hospital.”“The description resonates with the husband’s low awareness about the importance of his presence in maternal care. A recent systematic review and meta-analysis indicated that male involvement is associated with improved maternal health outcome in developing countries .Out of thirty-three women who wanted to deliver at the health facility, ten responded that due to the delayed arrival of a vehicle they had to deliver the baby at home. Eight women did not get enough time as “sudden delivery” took place, and in two cases the vehicle arrived after delivery. In short, a total of eighteen women could not go to institutions to deliver because the vehicle did not arrive in time. It is worth mentioning that during the FGDs, it was discovered that the reason for the delayed arrival of vehicles and inadequate time to call the vehicle had to do with reporting on birth preparedness. In the checklist for birth preparedness, women and the responsible family members are expected to know their Estimated Date of Delivery (EDD) and when the true delivery pain starts around EDD, women are expected to report to the ASHA or to household members. Then the household members or the ASHA make the necessary arrangements to call an ambulance or any other vehicle to transport the woman to the institution for delivery. However, the detection and reporting of the onset of true labour pain remains challenging.JSY program , the federal Indian government has introduced transport facilities for pregnant women. Universal availability of GPS fitted ambulances, reliable, assured free transport for pregnant women, clear policy articulation on entitlements, establishing control rooms for timely response and provision of services, drop back facility, a prudent mix of basic level ambulances and emergency response vehicles are some of the characteristics of the ambulances and referral transport facilities [On a given date, on the basis of Last Menstrual Period (LMP) date, physicians or trained community health workers calculate EDD and gestational age for the expectant mother . Howevercilities . The guicilities , althougcilities .This study highlights the preference for place of delivery and reaches the conclusion that women who undergo home delivery might prefer to go to a facility to deliver. Thus, if any surveys, especially cross-sectional surveys compile data on place of delivery without investigating women’s preference in place of delivery, researchers should be careful while explaining the individual factors associated with home delivery. Since health is a state subject in India, in order to realize the successful implementation of reproductive, maternal, newborn, child, and adolescent health (RMNCH+A),state governments  must pay attention in designing household-level interventions, focusing on the socioeconomic gradient of determining institutional delivery. With the help of village level health workers , and an intervention that focuses on educating pregnant women’s household members (focusing on husbands and mothers-in-law) on birth preparedness and reporting the onset of true labour pain, the level of institutional delivery can be increased. ASHAs should be trained to counsel household members of pregnant women. If the household members including the pregnant women have already decided to deliver the baby at home, ASHAs should pay special attention and inform the district health authority to take necessary action. In case of prior history of complications, ASHAs should regularly monitor the pregnant women and should make sure the pregnant woman is sent to the institution for delivery, well in advance.The findings of this study should be interpreted with the following limitations. First, the response on preferred place of delivery could be affected by recall errors as the women participating in the FGDs were asked to talk about their last delivery in the three years preceding the survey date, although training of data collectors, use of local events and provision of manuals for interviewing and the unforgettable nature of such major events play a considerable role in minimizing errors. Second, the information on preference for place of delivery could be affected by the social desirability bias as the respondents who had home delivery and who wanted to opt for institutional delivery were exposed to the fact that home delivery was an undesirable behaviour. Third, as the study sample was purposively selected, the findings of this study can only be generalized to settings with similar characteristics. Despite the above limitations, the design of the study (being community-based) to conduct FGDs has provided sufficient data to attain the study objective.S1 File(PDF)Click here for additional data file.


The European Union (EU) is a conglomerate of more than 500 million people, 19.2% (approximately 100 million) of whom are older adults . These fActive ageing is a multidimensional concept affected by several factors, including physical functionality, lifestyle, urban environment, and social inclusion , 5. In 2An operational definition of healthy ageing is still being debated, however, and consensus has not yet been achieved. McLaughlin and colleagues, who analysed the impact of different definitions of healthy ageing, concluded that a functional definition of health, i.e., free from symptomatic diseases and disabilities, may be acceptable . The valSeveral models have been proposed to measure AHA, however, consensus is needed to be able to implement specific actions , 15. TheAlthough life expectancy at birth has increased by approximately 3 years over the past decade, disability-free life expectancy  has not increased over this same time period . This phvia management of frailty at the community level. For example, the European Innovation Partnership on AHA gathers hundreds of public and private stakeholders from different backgrounds  to brainstorm and execute innovative solutions for AHA to be exchanged and implemented across different settings within Europe  Jordi Gol has developed a programme working with community nurses who provides elderly community members with advice on physical activities, diet, and medication schedule and also hold memory workshops: this programme reduced the use of health care services as well as the mortality rate of individuals over 65 years old in this community . The Univia the Internet), however, is deep; only approximately 45% of the over-65 population across Europe use the Internet at least once per week , outlined how digital innovation enabled by a functioning Digital Single Market can transform demographic changes into opportunities for Europe’s economy and society , 39 provper week , and in per week . The “BlThe health care market has not declined over the past 10 years despite the presence of a general economic crisis. The need for care has continued to increase as the population ages, and households are likely to invest more of their resources into this sector over the coming years. There is a window of opportunity, therefore, to implement programmes that proactively target the population at highest risk of frailty and functional decline, namely those over 75 years old. A large investment in health promotion and education that centres on strengthening health, ICT literacy, and social integration not only would serve as insurance for healthier old age and support for the sustainability of the European Health Systems, but also would offer significant occupational benefits to those who are interested in care services. Such programmes would require reorganisation of current models of care at the community level, and would also require individuals to change their view of AHA to that of a long-life approach based on health promotion and education.This debate emphasizes the key role of the determinants of health in AHA. In nineteenth century Europe, an improvement in socioeconomic conditions was the starting point for the most revolutionary demographic and epidemiologic transition in the contemporary age. Environmental sanitation and improved nutrition were the most important factors leading to this revolution at the population level. During this time, life expectancy increased from an average of 45 years to an average of approximately 80 years in most European countries. Europe was the first geographical area in the world to experience this success in life expectancy. Today, Europe continues to experience more advantages and more challenges with its ageing population than any other region in the world. Strengthening the social dimension of prevention programmes and changing the life styles represent key elements in improving quality of life and reducing the risk of loss of physical autonomy, especially among the over-75 population. These programmes can also provide occupational advantages across many European countries.A strong effort is needed to improve the integration of the growing number of older adults to avoid the negative consequences of social isolation, malnutrition, and reduced physical activity. In the era of technological development and personalised medicine, environmental and nutritional factors together with healthy lifestyles represent the most powerful factors that determine the health of a population, which is encouraging because these are factors that can be influenced by health promotion and educational intervention. The current weakness of the public health approach to the promotion of AHA which threatens the quality of life of European older adults as well as the medium- and long-term sustainability of the health systems. However, Europe is well-poised to play a leading role worldwide in facing the challenges of increasing HLY expectancy by taking advantage of its assets in knowledge and innovation.GL wrote the text. HC, MI, AP, and PK revised the text. FC, RC, EV, LP, MM, and RS contributed to the text with suggestions, comments, and proposals.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AZ and handling Editor declared their shared affiliation.


Melanoma is the deadliest form of skin cancer, and early detection is crucial for patient survival. Computer systems can assist in melanoma detection, but are not widespread in clinical practice. In 2016, an open challenge in classification of dermoscopic images of skin lesions was announced. A training set of 900 images with corresponding class labels and semi-automatic/manual segmentation masks was released for the challenge. An independent test set of 379 images, of which 75 were of melanomas, was used to rank the participants. This article demonstrates the impact of ranking criteria, segmentation method and classifier, and highlights the clinical perspective. We compare five different measures for diagnostic accuracy by analysing the resulting ranking of the computer systems in the challenge. Choice of performance measure had great impact on the ranking. Systems that were ranked among the top three for one measure, dropped to the bottom half when changing performance measure. Nevus Doctor, a computer system previously developed by the authors, was used to participate in the challenge, and investigate the impact of segmentation and classifier. The diagnostic accuracy when using an automatic versus the semi-automatic/manual segmentation is investigated. The unexpected small impact of segmentation method suggests that improvements of the automatic segmentation method w.r.t. resemblance to semi-automatic/manual segmentation will not improve diagnostic accuracy substantially. A small set of similar classification algorithms are used to investigate the impact of classifier on the diagnostic accuracy. The variability in diagnostic accuracy for different classifier algorithms was larger than the variability for segmentation methods, and suggests a focus for future investigations. From a clinical perspective, the misclassification of a melanoma as benign has far greater cost than the misclassification of a benign lesion. For computer systems to have clinical impact, their performance should be ranked by a high-sensitivity measure. Melanoma is the deadliest form of skin cancer. The survival rate drops as the level of tumour invasion increases, and therefore early detection is crucial for the patient’s survival , 2. MelaComputer systems for melanoma detection seek to correctly classify a lesion based on input and previous training. The ideal diagnostic test should have 100% sensitivity and 100% specificity. In medicine this is however almost never feasible. In the evaluation of clinical diagnostic aids for melanoma detection, the main priority is on increasing sensitivity as overlooking a melanoma may have a fatal outcome for the patient . In contThe input of the computer system is typically a dermoscopic image, but other technologies such as multispectral imaging and Rahman spectroscopy are also used. See e.g.,  and 7]  7] for aResearch and development of computer systems for melanoma detection have increased in the past few decades, following the development of digital cameras and attachable dermoscopes. An overview can be found in . DespiteSmall data sets result in training and testing on the same data, often by incorrect use of cross-validation. This gives overly optimistic estimates of the test error , 10, andThe diagnostic difficulty of the data set has significant impact on the reported diagnostic accuracy of the system, as discussed in , and ill2 data set was made publicly available 19]. The For participation in the challenge, semi-automatic feature selection was conducted on the basis of the 900 training images, following the procedure described in . Apart fThe prior class probability in a discriminant analysis classifier can be estimated based on the class labels in the training set. The output of the classifier is the posterior probability of an observation belonging to a certain class. For calculation of sensitivity values from 0% to 100%, the threshold for the posterior probability is adjusted from 0 to 1. Another option is to adjust the prior probability for the class from 0 to 1. For this paper, we have recalculated the high-sensitivity measures by adjusting the prior probability to avoid the situation where several lesions have the saturated posterior probability of 1.00.The challenge were provided as well. This made it possible to rank the participants according to several criteria, not only the one chosen by the challenge. Average precision and AUC of ROC are global performance measures, from 0% sensitivity (no melanomas detected), to 100% sensitivity . The high-sensitivity measures provide performance measures given that a high proportion of the melanomas is detected.The participants were ranked according to diagnostic accuracy of the test set. Other aspects such as computation time were not considered. The challenge’s ranking criterion was average precision, but scores for the other performance measures listed in Section For those participants that were ranked highest by one of the measures, From From The algorithms for the challenge participants were not submitted, and therefore we investigated the impact of segmentation for Nevus Doctor. The occasionally failed segmentation does not seem to have an impact on the classification result. Because segmentation method had lesser impact than expected, we investigated the impact of classifier algorithm. The performance of a classifier is tightly connected to the characteristics of the features, and it is therefore difficult to rank classifiers. The differences in performance can be the result of the features being more suited to a certain classifier, and the ranking might change if other features are made available.We therefore investigate the performance of a few fairly similar classifiers. The aim is not to rank the classifiers for melanoma detection, but to investigate how the performance of a system changes by using a different classifier.When training Nevus Doctor for the challenge, LDA and QDA classifiers were considered, and QDA was used on the test set. In addition, we have investigated the diagonal LDA and QDA (dLDA and dQDA) classifiers, which correspond to naive Bayes classifiers. The features were not reselected, and therefore, QDA has a slight benefit. The results are shown in The ISIC data repository, consisting of more than 12,000 dermoscopic images, has answered to a need expressed for several years in the field of computer aided melanoma detection: a publicly available data set. Two important outcomes of collecting and sharing data are: (1) Large data sets allow for large training sets and independent test sets. (2) Public availability allows for comparison of algorithms on the same data. The ISBI challenge has taken advantage of this and set aside an independent test set, and ranked its participants according to diagnostic accuracy. However, we see from In this challenge, the systems were ranked according to average precision, which weights misclassifications equally whether it is a melanoma misclassified as benign, or a benign lesion misclassified as malignant. Specificity score at high sensitivity takes into account that a melanoma misclassified as benign can have fatal outcome for the patient, and has been used in clinical studies for melanoma detection , 12. A pFrom Tables In An important question when analysing the diagnostic accuracy, whatever performance measure, is its generalisability to other data sets. Ideally, the results should reflect a system’s performance under actual clinical conditions. The test set in this challenge was not consecutively collected, and inclusion and exclusion criteria are not stated (e.g. if non-melanoma skin cancers are excluded). Even though the performance in absolute numbers, e.g. specificity at 95% sensitivity, are better for many of the systems in this challenge compared to other studies, one cannot draw any conclusions.Demanding more information can result in fewer deposits to the repository, but to have clinical impact, a minimum of clinical information is essential. See e.g.,  for recoThe ISIC Data Archive consists of images taken with different cameras and dermoscopes, and from different populations, unlike many commercial systems that require the use of a certain camera and dermoscope. Robustness to variability in equipment is beneficial, due to the fast development of camera and dermoscope technologies, giving the system the ability to easily adapt to new equipment, without an extensive training set. However, it introduces some obstacles because the size and colour of a lesion have diagnostic importance, but are not consistent between different cameras and dermoscopes. Different image resolutions, magnifications and distances to the skin result in the true size of the lesion differing from image to image, though this can be solved easily by providing information regarding pixels per mm. Additional aspects that pose a challenge are the different colour calibrations of the cameras and different light sources, as illustrated in For the recent years, deep convolutional neural networks (CNN) have entered the field of image classification with great success, and has also been applied to melanoma detection . In thisComputer systems for melanoma detection have considerably lower diagnostic accuracy than the current gold standard (histopathology), and can only provide decision support, not actual diagnosis. The usefulness of a system relies not only on its ability for correct classification but also on the possibility for the user to take advantage of the output. To truly know whether a system can have clinical impact, it must be tested in a clinical setting, which is not feasible for an open challenge.Skin Lesion Analysis towards Melanoma Detection challenge has resulted in the largest comparison between computer systems for dermoscopic images, both in number of participants and in test set size. Whereas the obstacle of small datasets and non-comparable results are solved with a public repository and an open challenge, the question of performance measure still remains. This article has investigated accuracy measures’ impact on classification performance ranking, and has thus highlighted a choice that is seldom under careful consideration. From a clinical perspective, the misclassification of a melanoma as benign has far greater cost than the misclassification of a benign lesion as malignant. A system with 95% sensitivity misclassifies one in 20 melanomas, and it is difficult to imagine that lower sensitivity is acceptable, and global measures of accuracy are not clinically relevant. We suggest a specificity score for a fixed sensitivity of at least 95%, calculated by the use of cross-validation, alternatively the AUC of ROC calculated from 95% to 100% sensitivity, also using cross-validation. A high-sensitivity measure can improve the clinical relevance of the challenge, and help ISIC to achieve its goal “to help reduce melanoma mortality” (http://isdis.net/isic-project/).The


When we began this process, we were doctoral students and a faculty member in a research methods course. As students, we were facing a review of the literature for our dissertations. We encountered several different ways of conducting a review but were unable to locate any resources that synthesized all of the various synthesis methodologies. Our purpose is to present a comprehensive overview and assessment of the main approaches to research synthesis. We use ‘research synthesis’ as a broad overarching term to describe various approaches to combining, integrating, and synthesizing research findings.We conducted an integrative review of the literature to explore the historical, contextual, and evolving nature of research synthesis. We searched five databases, reviewed websites of key organizations, hand-searched several journals, and examined relevant texts from the reference lists of the documents we had already obtained.We identified four broad categories of research synthesis methodology including conventional, quantitative, qualitative, and emerging syntheses. Each of the broad categories was compared to the others on the following: key characteristics, purpose, method, product, context, underlying assumptions, unit of analysis, strengths and limitations, and when to use each approach.The current state of research synthesis reflects significant advancements in emerging synthesis studies that integrate diverse data types and sources. New approaches to research synthesis provide a much broader range of review alternatives available to health and social science students and researchers. For example, the Severe Acute Respiratory Syndrome (SARS) epidemic in Canada in 2002-2003, the recent Ebola epidemic in Africa, and the ongoing HIV/AIDs pandemic are global health concerns. There have also been dramatic increases in the prevalence of chronic diseases around the world As doctoral nursing students facing a review of the literature for our dissertations, and as a faculty member teaching a research methods course, we encountered several ways of conducting a research synthesis but found no comprehensive resources that discussed, compared, and contrasted various synthesis methodologies on their purposes, processes, strengths and limitations. To complicate matters, writers use terms interchangeably or use different terms to mean the same thing, and the literature is often contradictory about various approaches. Some texts Research synthesis is relatively new in public health but has a long history in other fields dating back to the late 1800s. Research synthesis, a research process in its own right 2.Research synthesis is the overarching term we use to describe approaches to combining, aggregating, integrating, and synthesizing primary research findings. Each synthesis methodology draws on different types of findings depending on the purpose and product of the chosen synthesis . This search yielded very few texts on some methodologies and many on others. We realized that many documents on research synthesis had not been picked up in the search. Therefore, we also searched Google Scholar, PubMed, ERIC, and Social Science Index, as well as the websites of key organizations such as the Joanna Briggs Institute, the University of York Centre for Evidence-Based Nursing, and the Cochrane Collaboration database. We hand searched several nursing, social science, public health and health policy journals. Finally, we traced relevant documents from the references in obtained texts.Over the period of 2008 to 2012 we extensively searched the literature, updating our search at several time points, not restricting our search by date. The dates of texts reviewed range from 1967 to 2015. We used the terms above combined with the term “method*  in the database We included works that met the following inclusion criteria: (1) published in English; (2) discussed the history of research synthesis; (3) explicitly described the approach and specific methods; or (4) identified issues, challenges, strengths and limitations of the particular methodology. We excluded research reports that resulted from the use of particular synthesis methodologies unless they also included criteria 2, 3, or 4 above.Based on our search, we identified additional types of research synthesis . Still, we missed some important developments in meta-analysis, for example, identified by the journal's reviewers that have now been discussed briefly in the paper. The final set of 197 texts included in our review comprised theoretical, empirical, and conceptual papers, books, editorials and commentaries, and policy documents.In our preliminary review of key texts, the team inductively developed a framework of the important elements of each method for comparison. In the next phase, each text was read carefully, and data for these elements were extracted into a table for comparison on the points of: key characteristics, purpose, methods, and product; see 4.We identified four broad categories of research synthesis methodology: Conventional, quantitative, qualitative, and emerging syntheses. From our dataset of 197 texts, we had 14 texts on conventional synthesis, 64 on quantitative synthesis, 78 on qualitative synthesis, and 41 on emerging syntheses. Although we group these types of synthesis into four broad categories on the basis of similarities, each type within a category has unique characteristics, which may differ from the overall group similarities. Each could be explored in greater depth to tease out their unique characteristics, but detailed comparison is beyond the scope of this article.4.14.1.1integrative or interpretive.  have typically used purely quantitative data . More recently, both Cochrane 4.1.3Four types of research questions direct inquiry across the different types of syntheses. The first is a well-developed research question that gives direction to the synthesis . The second begins as a broad general question that evolves and becomes more refined over the course of the synthesis . In the third type, the synthesis begins with a phenomenon of interest and the question emerges in the analytic process . Lastly, there is no clear question, but rather a general review purpose . Thus, the requirement for a well-defined question cuts across at least three of the synthesis types .4.1.4This is a contested issue within and between the four synthesis categories. There are strong proponents of quality appraisal in the quantitative traditions of systematic review and meta-analysis based on the need for strong studies that will not jeopardize validity of the overall findings. Nonetheless, there is no consensus on pre-defined criteria; many scales exist that vary dramatically in composition. This has methodological implications for the credibility of findings Specific methodologies from the conventional, qualitative, and emerging categories support quality appraisal but do so with caveats. In conventional integrative reviews appraisal is recommended, but depends on the sampling frame used in the study There is no agreement on quality appraisal among qualitative meta-ethnographers with some supporting and others refuting the need for appraisal. 4.2All research syntheses share a common purpose -- to summarize, synthesize, or integrate research findings from diverse studies. This helps readers stay abreast of the burgeoning literature in a field. Our discussion here is at the level of the four categories of synthesis. Beginning with conventional literature syntheses, the overall purpose is to attend to mature topics for the purpose of re-conceptualization or to new topics requiring preliminary conceptualization The purpose of quantitative systematic reviews is to combine, aggregate, or integrate empirical research to be able to generalize from a group of studies and determine the limits of generalization The purpose of qualitative syntheses is broadly to synthesize complex health experiences, practices, or concepts arising in healthcare environments. There may be various purposes depending on the qualitative methodology. For example, in hermeneutic studies the aim may be holistic explanation or understanding of a phenomenon The overarching purpose of emerging syntheses is challenging the more traditional types of syntheses, in part by using data from both quantitative and qualitative studies with diverse designs for analysis. Beyond this, however, each emerging synthesis methodology has a unique purpose. In meta-narrative review, the purpose is to identify different research traditions in the area, synthesize a complex and diverse body of research. Critical interpretive synthesis shares this characteristic. Although a distinctive approach, critical interpretive synthesis utilizes a modification of the analytic strategies of meta-ethnography 4.34.3.1There are varying degrees of systematization across the categories of research synthesis. The most systematized are quantitative systematic reviews and meta-analyses. There are clear processes in each with judgments to be made at each step, although there are no agreed upon guidelines for this. The process is inherently subjective despite attempts to develop objective and systematic processes In comparison with some types of qualitative synthesis, concept analysis is quite procedural. Qualitative meta-synthesis also has defined procedures and is systematic, yet perhaps less so than concept analysis. Qualitative meta-synthesis starts in an unsystematic way but becomes more systematic as it unfolds. Procedures and frameworks exist for some of the emerging types of synthesis e.g., but are 4.3.2Some synthesis processes are considerably more complex than others. Methodologies with clearly defined steps are arguably less complex than the more flexible and emergent ones. We know that any study encounters challenges and it is rare that a pre-determined research protocol can be followed exactly as intended. Not even the rigorous methods associated with Cochrane 4.4The products of research syntheses usually take three distinct formats . Quantitative systematic reviews and meta-analyses have typically been conducted on studies using experimental and quasi-experimental designs and more recently observational studies, which control for contextual features to allow for understanding of the ‘true’ effect of the intervention More recently, systematic reviews have included covariates or mediating variables  to help explain variability in the results across studies When conventional literature reviews incorporate studies that deal with context, there is a place for considering contextual influences on the intervention or phenomenon. Reviews of quantitative experimental studies tend to be devoid of contextual considerations since the original studies are similarly devoid, but context might figure prominently in a literature review that incorporates both quantitative and qualitative studies.Qualitative syntheses have been conducted on the contextual features of a particular phenomenon Meta-narrative synthesis More recent iterations of concept analysis Realist synthesis 4.6When we began our review, we ‘assumed’ that the assumptions underlying synthesis methodologies would be a distinguishing characteristic of synthesis types, and that we could compare the various types on their assumptions, explicit or implicit. We found, however, that many authors did not explicate the underlying assumptions of their methodologies, and it was difficult to infer them. Kirkevold Authors of some emerging synthesis approaches have been very explicit about their assumptions and philosophical underpinnings. An implicit assumption of most emerging synthesis methodologies is that quantitative systematic reviews and meta-analyses have limited utility in some fields [e.g., in public health –Realist synthesis is philosophically grounded in critical realism or, as noted above, a realist logic of inquiry Meta-narrative synthesis is explicitly rooted in a constructivist philosophy of science In the case of purely quantitative or qualitative syntheses, it may be an easier matter to uncover unstated assumptions because they are likely to be shared with those of the primary studies in the genre. For example, grounded formal theory shares the philosophical and theoretical underpinnings of grounded theory, rooted in the theoretical perspective of symbolic interactionism As with meta-narrative synthesis, meta-study developers identify constructivism as their interpretive philosophical foundation 4.7The unit of analysis for each category of review is generally distinct. For the emerging synthesis approaches, the unit of analysis is specific to the intention. In meta-narrative synthesis it is the storyline in diverse research traditions; in rapid review or scoping review, it depends on the focus but could be a concept; and in realist synthesis, it is the theories rather than programs that are the units of analysis. The elements of theory that are important in the analysis are mechanisms of action, the context, and the outcome For qualitative synthesis, the units of analysis are generally themes, concepts or theories, although in meta-study, the units of analysis can be research findings , research methods (“meta-method”) or philosophical/theoretical perspectives (“meta-theory”) 4.8In this section, we discuss the overarching strengths and limitations of synthesis methodologies as a whole and then highlight strengths and weaknesses across each of our four categories of synthesis.4.8.1With the vast proliferation of research reports and the increased ease of retrieval, research synthesis has become more accessible providing a way of looking broadly at the current state of research. The availability of syntheses helps researchers, practitioners, and policy makers keep up with the burgeoning literature in their fields without which evidence-informed policy or practice would be difficult. Syntheses explain variation and difference in the data helping us identify the relevance for our own situations; they identify gaps in the literature leading to new research questions and study designs. They help us to know when to replicate a study and when to avoid excessively duplicating research. Syntheses can inform policy and practice in a way that well-designed single studies cannot; they provide building blocks for theory that helps us to understand and explain our phenomena of interest.4.8.2The process of selecting, combining, integrating, and synthesizing across diverse study designs and data types can be complex and potentially rife with bias, even with those methodologies that have clearly defined steps. Just because a rigorous and standardized approach has been used does not mean that implicit judgements will not influence the interpretations and choices made at different stages.In all types of synthesis, the quantity of data can be considerable, requiring difficult decisions about scope, which may affect relevance. The quantity of available data also has implications for the size of the research team. Few reviews these days can be done independently, in particular because decisions about inclusion and exclusion may require the involvement of more than one person to ensure reliability.For all types of synthesis, it is likely that in areas with large, amorphous, and diverse bodies of literature, even the most sophisticated search strategies will not turn up all the relevant and important texts. This may be more important in some synthesis methodologies than in others, but the omission of key documents can influence the results of all syntheses. This issue can be addressed, at least in part, by including a library scientist on the research team as required by some funding agencies. Even then, it is possible to miss key texts. In this review, for example, because none of us are trained in or conduct meta-analyses, we were not even aware that we had missed some new developments in this field such as meta-regression One limitation of systematic reviews and meta-analyses is that they rapidly go out of date. We thought this might be true for all types of synthesis, although we wondered if those that produce theory might not be somewhat more enduring. We have not answered this question but it is open for debate. For all types of synthesis, the analytic skills and the time required are considerable so it is clear that training is important before embarking on a review, and some types of review may not be appropriate for students or busy practitioners.Finally, the quality of reporting in primary studies of all genres is variable so it is sometimes difficult to identify aspects of the study essential for the synthesis, or to determine whether the study meets quality criteria. There may be flaws in the original study, or journal page limitations may necessitate omitting important details. Reporting standards have been developed for some types of reviews ; but there are no agreed upon standards for qualitative reviews. This is an important area for development in advancing the science of research synthesis.4.8.3conventional literature review and now the increasingly common integrative review remain important and accessible approaches for students, practitioners, and experienced researchers who want to summarize literature in an area but do not have the expertise to use one of the more complex methodologies. Carefully executed, such reviews are very useful for synthesizing literature in preparation for research grants and practice projects. They can determine the state of knowledge in an area and identify important gaps in the literature to provide a clear rationale or theoretical framework for a study The Generally, conventional reviews include diverse study designs and data types that facilitate comprehensiveness, which may be a strength on the one hand, but can also present challenges on the other. The complexity inherent in combining results from studies with diverse methodologies can result in bias and inaccuracies. The absence of clear guidelines about how to synthesize across diverse study types and data Quantitative systematic reviews and meta-analyses have been important in launching the field of evidence-based healthcare. They provide a systematic, orderly and auditable process for conducting a review and drawing conclusions Despite their strengths, they also have limitations. Systematic reviews and meta-analyses do not provide a way of including complex literature comprising various types of evidence including qualitative studies, theoretical work, and epidemiological studies. Only certain types of design are considered and qualitative data are used in a limited way. This exclusion limits what can be learned in a topic area.Meta-analyses are often not possible because of wide variability in study design, population, and interventions so they may have a narrow range of utility. New developments in meta-analysis, however, can be used to address some of these limitations. Network meta-analysis is used to explore relative efficacy of multiple interventions, even those that have never been compared in more conventional pairwise meta-analyses Some have accused meta-analysis of combining apples and oranges The usefulness of systematic reviews in synthesizing complex health and social interventions has also been challenged Qualitative syntheses may be the type of review most fraught with controversy and challenge, while also bringing distinct strengths to the enterprise. Although these methodologies provide a comprehensive and systematic review approach, they do not generally provide definitive statements about intervention effectiveness. They do, however, address important questions about the development of theoretical concepts, patient experiences, acceptability of interventions, and an understanding about why interventions might work.Most qualitative syntheses aim to produce a theoretically generalizable mid-range theory that explains variation across studies. This makes them more useful than single primary studies, which may not be applicable beyond the immediate setting or population. All provide a contextual richness that enhances relevance and understanding. Another benefit of some types of qualitative synthesis  is that the concept of saturation provides a sound rationale for limiting the number of texts to be included thus making reviews potentially more manageable. This contrasts with the requirements of systematic reviews and meta-analyses that require an exhaustive search.Qualitative researchers debate about whether the findings of ontologically and epistemological diverse qualitative studies can actually be combined or synthesized Emerging synthesis methodologies were developed to address some limitations inherent in other types of synthesis but also have their own issues. Because each type is so unique, it is difficult to identify overarching strengths of the entire category. An important strength, however, is that these newer forms of synthesis provide a systematic and rigorous approach to synthesizing a diverse literature base in a topic area that includes a range of data types such as: both quantitative and qualitative studies, theoretical work, case studies, evaluations, epidemiological studies, trials, and policy documents. More than conventional literature reviews and systematic reviews, these approaches provide explicit guidance on analytic methods for integrating different types of data. The assumption is that all forms of data have something to contribute to knowledge and theory in a topic area. All have a defined but flexible process in recognition that the methods may need to shift as knowledge develops through the process.Many emerging synthesis types are helpful to policy makers and practitioners because they are usually involved as team members in the process to define the research questions, and interpret and disseminate the findings. In fact, engagement of stakeholders is built into the procedures of the methods. This is true for rapid reviews, meta-narrative syntheses, and realist syntheses. It is less likely to be the case for critical interpretive syntheses.Another strength of some approaches  is that quality and publication standards have been developed to guide researchers, reviewers, and funders in judging the quality of the products There are also challenges of these new approaches. The methods are new and there may be few published applications by researchers other than the developers of the methods, so new users often struggle with the application. The newness of the approaches means that there may not be mentors available to guide those unfamiliar with the methods. This is changing, however, and the number of applications in the literature is growing with publications by new users helping to develop the science of synthesis e.g.,. However4.9Choosing an appropriate approach to synthesis will depend on the question you are asking, the purpose of the review, and the outcome or product you want to achieve. In If researchers' concern is to develop theory, they might consider qualitative syntheses or some of the emerging syntheses that produce theory . If the aim is to track the development and evolution of concepts, theories or ideas, or to determine how an issue or question is addressed across diverse research traditions, then meta-narrative synthesis would be most appropriate.When the purpose is to review the literature in advance of undertaking a new project, particularly by graduate students, then perhaps an integrative review would be appropriate. Such efforts contribute towards the expansion of theory, identify gaps in the research, establish the rationale for studying particular phenomena, and provide a framework for interpreting results in ways that might be useful for influencing policy and practice.For researchers keen to bring new insights, interpretations, and critical re-conceptualizations to a body of research, then qualitative or critical interpretive syntheses will provide an inductive product that may offer new understandings or challenges to the status quo. These can inform future theory development, or provide guidance for policy and practice.5.What is the current state of science regarding research synthesis? Public health, health care, and social science researchers or clinicians have previously used all four categories of research synthesis, and all offer a suitable array of approaches for inquiries. New developments in systematic reviews and meta-analysis are providing ways of addressing methodological challenges 5.1We raise the question of whether it is possible or desirable to find all available studies for a synthesis that has this requirement  definition of knowledge translation (KT), research or knowledge synthesis is an integral component Research synthesis neither makes research more applicable to practice nor ensures implementation. Focus must now turn seriously towards translation of synthesis findings into knowledge products that are useful for health care practitioners in multiple areas of practice and develop appropriate strategies to facilitate their use. The burgeoning field of knowledge translation has, to some extent, taken up this challenge; however, the research-practice gap continues to plague us 5.4Our study took longer than would normally be expected for an integrative review. Each of us were primarily involved in our own dissertations or teaching/research positions, and so this study was conducted ‘off the sides of our desks.’ A limitation was that we searched the literature over the course of 4 years (from 2008–2012), necessitating multiple search updates. Further, we did not do a comprehensive search of the literature after 2012, thus the more recent synthesis literature was not systematically explored. We did, however, perform limited database searches from 2012–2015 to keep abreast of the latest methodological developments. Although we missed some new approaches to meta-analysis in our search, we did not find any new features of the synthesis methodologies covered in our review that would change the analysis or findings of this article. Lastly, we struggled with the labels used for the broad categories of research synthesis methodology because of our hesitancy to reinforce the divide between quantitative and qualitative approaches. However, it was very difficult to find alternative language that represented the types of data used in these methodologies. Despite our hesitancy in creating such an obvious divide, we were left with the challenge of trying to find a way of characterizing these broad types of syntheses.6.Our findings offer methodological clarity for those wishing to learn about the broad terrain of research synthesis. We believe that our review makes transparent the issues and considerations in choosing from among the four broad categories of research synthesis. In summary, research synthesis has taken its place as a form of research in its own right. The methodological terrain has deep historical roots reaching back over the past 200 years, yet research synthesis remains relatively new to public health, health care, and social sciences in general. This is rapidly changing. New developments in systematic reviews and meta-analysis, and the emergence of new synthesis methodologies provide a vast array of options to review the literature for diverse purposes. New approaches to research synthesis and new analytic methods within existing approaches provide a much broader range of review alternatives for public health, health care, and social science students and researchers.


Cancer research has become a global enterprise, and the number of researchers, as well as the cost for their activities, has skyrocketed. The budget for the National Cancer Institute of the United States National Institutes of Health alone was US$5.2 billion in 2015. Since most of the research is funded by public money, it is perfectly legitimate to ask if these large expenses are worth it. In this brief commentary, we recapitulate some of the breakthroughs that mark the history of breast cancer research over the past decades and emphasize the resulting benefits for afflicted women. In 1971, only 40% of women diagnosed with breast cancer would live another 10 years. Today, nearly 80% of women reach that significant milestone in most developed countries. This dramatic change has afforded breast cancer patients many productive years and a better quality of life. Progress resulted largely from advances in the understanding of the molecular details of the disease and their translation into innovative, rationally designed therapies. These developments are founded on the revolution in molecular and cellular biology, an entirely new array of methods and technologies, the enthusiasm, optimism, and diligence of scientists and clinicians, and the considerable funding efforts from public and private sources. We were lucky to be able to spend our productive years in a period of scientific upheaval in which methods and concepts were revolutionized and that allowed us to contribute, within the global scientific community, to the progress in basic science and clinical practice. Such progress has allowed breast cancer patients to enjoy many more productive years and a better quality of life. What happened during that time interval, and what were the most important breakthroughs? The advances in understanding the basic molecular details of the disease were the driving force. These new insights were translated into innovative drug development and clinical studies and gradually led to progress in prevention, diagnosis, and treatment. However, 45 years ago, this path was far from clear for the experimental and clinical researchers who worked in the field. Dead ends, deviations, oversimplified concepts of the nature of the disease, and exaggerated expectations by the general public and the scientific community were constant companions of the research process. They were overcome by optimism, persistence, and diligence on the side of the researchers, driven by concurrent developments of methods and technologies, and finally enabled by considerable funding efforts of public and private agencies.In 1971, only 40% of the women diagnosed with breast cancer could expect to survive this terrible finding for 10 years. This number has increased dramatically over the last 45 years. Today, nearly 80% of afflicted women reach this milestone in most developed countries , which is transmitted through the milk of certain strains of mice, causing mammary cancer in their offspring. Many researchers, us included, expected that it would be possible to extrapolate the findings from mouse mammary tumors to human cancers. The hope was to find the human equivalent, i.e., a breast-cancer-causing virus, and use appropriate vaccination procedures or other antiviral strategies to protect women from viral infection and subsequently from the development of breast cancer. In the end, crucial differences between mice and men prevailed, and the human equivalent of MMTV is still elusive . Was theThese insights, important for the understanding of the transcriptional regulation of gene expression by steroid hormones, found their way back to cancer research. Transcription factors, molecules that bind to specific DNA elements in promoter regions of particular target genes and induce the transcription of mRNA, were identified, among them the estrogen receptor. This receptor is normally present in the cell as a latent molecule, but can be activated through its association with a small hormone ligand, estrogen. A large fraction of breast cancer cells are utterly dependent on the transcriptional activating function of the estrogen receptor. This insight goes back to the observations made by the surgeon George Beatson more than 100 years ago. He showed that removal of the ovaries, the major source of estradiol, could lead to breast cancer regression.Targeting the estrogen receptor became a therapeutic strategy in the 1960s. Variants of the estrogen molecule, which retain the ability to bind to the estrogen receptor but fail to activate it, were synthesized; one of these was named tamoxifen. These molecules mask the estrogen receptor and prevent estrogen action. Tamoxifen has become a widely used drug for the adjuvant treatment of patients in whom the tumor cells express the estrogen receptor . TamoxifThe suppression of estrogen action in breast cancer cells has been complemented in recent years by inhibitors of aromatase. This enzyme participates in the local production of estrogen in tumor cells of postmenopausal patients. Counteracting the growth-promoting effects of local estrogen production is an effective weapon for clinicians and has been associated with relatively mild side effects for patients. Endocrine antagonists can be considered pioneers of the concept of “targeted therapy” . UnfortuCells are constantly communicating with their environment, and many of the molecular signals and mechanisms constituting the communication networks between cells have been elucidated in the past decades. Cells are “wired;” they constantly recognize signals and send out signals. These events are encoded in molecular signal transduction cascades that eventually determine the cellular phenotypes. Crucial insights into the communication mechanisms of breast cancer cells, particularly through their cell surface receptor signaling, have contributed greatly to progress in breast cancer therapy. Differently from the estrogen receptor, which acts as a transcription factor in the nucleus, cell surface receptors establish links between the extracellular environment and the intracellular signal transduction events. These receptors are anchored in the cell membrane and contain extracellular and intracellular domains. They sense signal molecules, e.g., growth factors or cytokines, through their extracellular domain and generate intracellular signals that, through a cascade of biochemical reactions, regulate cell survival and cell growth. The hyperactivity of such receptors can be a cause of cancer. In the 1980s and 1990s, researchers identified a large number of such receptors and characterized the intracellular signals emanating from their activation.One particular receptor, ErbB2, a member of the receptor tyrosine kinase family, was found in the mid-1980s to be overexpressed in about 25% of breast cancer cases. Importantly, clinical results supported the relevance of overexpressed ErbB2, which has become an extremely important drug target that has proved most beneficial for cancer therapy [The “story” of ErbB2 targeting also became one of the first examples for the strategy in which molecular diagnosis and targeted therapy have been successfully combined. ErbB2 expression can be determined in breast tumor tissues biopsies, and only the subpopulation of patients in whom the receptor is strongly expressed have a good chance to benefit from the antibody treatment. The prospective identification of patients most likely to respond to a particular targeted drug has important implications, not only for the choice of first-line therapy, but also for health economics. Subsequently, therapeutic strategies based on different molecular principles have been used in combination . For exaInsights into the intracellular signaling events triggered by cell surface receptor activation opened another avenue for treatment advances. Most growth factor receptors set in motion an intracellular signaling cascade through the activation of their tyrosine kinase in the intracellular domain; tyrosine kinases are enzymes that phosphorylate substrate molecules on tyrosine residues. Agents interfering with the enzymatic activity of specific tyrosine kinases can block the signaling pathways activated by the receptors, for example, ErbB2. In addition, since many of the downstream steps in the signaling pathways involve protein kinases, researchers could develop targeted drugs for nearly every step in the signal transduction cascades. Such drugs, in combination with advanced molecular diagnostics that provide insights into the deregulation of signaling in particular cancer cells, will further improve our therapeutic capabilities .Despite these achievements, we have certainly not reached the final goal, which is the prevention and cure of cancer, and there are many open questions. Is further progress to be expected? From which area of research will it come? A number of research directions appear most promising and are giving cause for optimism. Large-scale sequencing efforts provide high-resolution views into the mutational events in breast cancer cells. Numerous base substitutions, insertions, deletions, and structural variations have been found. From these genetic aberrations, we can deduce the deregulation of crucial biochemical processes in cancer cells. Recently, the entire genomes of 560 breast cancer cases have been deciphered and 93 altered “driver” genes have been identified. These genes are most likely causally involved in the genesis of the disease. Their identification also deepens our understanding of the causes of breast cancer and provides new targets for drugs that interfere with cancer growth . These pBRCA1 and BRCA2 genes account for 2%–3% of all cases of breast cancer. The early identification of women who are affected with a BRCA mutation can guide the management of cancer risk and can have a significant impact on the morbidity and mortality of BRCA carriers. The current risk management recommendations for breast cancer comprise preventive therapy with selective estrogen receptor modulators (SERMs), and considerable reductions in overall breast cancer incidence have been observed. Despite the decreased probability for developing breast cancer, only about 15% of the women made use of the preventive therapy even after genetic counseling [However, despite these therapeutic advances, a most disturbing aspect of tumor biology remains. The decline in breast cancer mortality over the last 45 years is impressive, but the incidence still continues to rise. For this reason, progress in cancer prevention becomes a most urgent task. Geneticists have uncovered a few of the determinants that predispose women to breast cancer. Functional variants of the Will we succeed in taking the final step and increase the 10-year survival rate to 100%? The prospects are encouraging. The development of targeted agents, immunological strategies, and preventive measures will individually, and in combination, lead to improved therapies and to a further decline in incidence rates. The advances we've yet to see, like the advances in treatment and the gains in life expectancy and quality of life that breast cancer patients experience today, will come from the efforts and insights provided by dedicated scientists and clinicians. They could not have been planned 45 years ago and reflect much serendipity and ingenuity, defining the way we do basic research. We may not know exactly what discoveries will ultimately help patients, and society at large, but history shows that money spent on basic cancer research is money well spent.


Addressing opioid use disorder has become a priority in Ontario, Canada, because of its high economic, social and health burden. There continues to be stigma and criticism relating to opioid use disorder and treatment options. The result has been unsystematic, partial, reactive policies and programs developed based on divergent points of view. The aim of this manuscript is to describe how past and present understandings, narratives, ideologies and discourse of opioid use, have impacted policies over the course of the growing opioid crisis.Assessing the impact of policy is complex. It involves consideration of conceptual issues of what impacts policy change. In this manuscript we argue that the development of polices and initiatives regarding opioids, opioid use disorder and opioid agonist treatment in the last decade, have been more strongly associated with the evolution of ideas, narratives and discourses rather than research relating to opioids. We formulate our argument using a framework by Sumner, Crichton, Theobald, Zulu, and Parkhurs. We use examples from the Canadian context to outline our argument such as: the anti- drug legislation from the Canadian Federal Conservative government in 2007; the removal of OxyContin™ from the drug formulary in 2012; the rapid expansion of opioid agonist treatment beginning in the early 2000s, the unilateral decision made regarding fee cuts for physicians providing opioid agonist treatment in 2015; and the most recent implementation of a narcotics monitoring system, which are all closely linked with the shifts in public opinion and discourse at the time of which these policies and programs are implemented.We conclude with recommendations to consider a multifactorial response using evidence and stakeholder engagement to address the opioid crisis, rather than a reactive policy approach. We suggest that researchers have an important role in shaping future policy by reframing ideas through knowledge translation, formation of values, creation of new knowledge and adding to the quality of public discourse and debate. Opioid Use Disorder (OUD) continues to be a health concern in Canada and the United States –5. The pThe opioid epidemic is a complex, multicomponent issue. For example, over 50% of individuals with OUD also have a mental health disorder . In factSubstance dependence, such as OUD, has been and continues to be highly stigmatized, has risen to national and international policy agendas. Sadly, perhaps one of the largest barriers limitting our collective ability to address the opioid crisis in Ontario, Canada, is the lack of consensus of the extent of the problem and uncoordinated ideas of appropriate solutions. For instance the perception of appropriate solutions to address the opioid crisis in the eyes of law enformcement, medicine, pharmacology, community programs, public health and health policy, are sometimes incompatible –16. FurtOpioid agonist treatment (OAT), and harm reduction, are critical parts of the strategy to address the epidemic of opioids. OAT is currently the standard of care and the intervention with the best evidence for long term patient safety, social wellness, and physical health benefits for the treatment of OUD . For thiEvidence to support the efficacy of OAT is well established in the academic literature. In a systematic literature review by Mattick, Been, Kimber and Davoli, 2009, methadone was statistically significantly more effective than non-pharmacological approaches in retaining patients in treatment and in the suppression of heroin use in 6 randomized control trials (RR = 0.66 95% CI 0.56–0.78). A cohort study, Ball and Ross, 1991, indicated that long term OAT was associated with a 97% decline in illicit opioid use. In the same study, 18.6% of patients reported ceasing intravenous drug use upon their admission to the OAT program. Importantly, Ball and Ross, followed patients after they dropped out of treatment and discovered that 82% of the drop out cohort had relapsed after 10 to 12 months being out of treatment , 17, 19.OAT remains the clinical strategy with the best evidence to support its effectiveness , but it OAT is expanding in Canada; yet, there continues to be a discrepancy between research and policy ideas . There cIn the last decade or so, public opinion of opioid use has shifted from the discussion of drug users as criminals, and the fear of narcotics , addictiIn 2006, under Federal legislative authority, the notion of drug users as criminals was reinforced with policies implemented by the Conservative Party of Canada throughout their 10-year term, but specifically in October of 2007 with the release of a National Anti-Drug Strategy . This waIn 2012, the idea that one drug was to blame for the increasing opioid issue was reinforced by the removal of OxyContin™ from the Ontario Drug Benefit Formulary 12 years after being introduced . Less thThe impacts of new policies are difficult to measure, however, with more public consultation, those involved in the decision to remove OxyContin™ may have gained insight on the potential effects of this policy on patients and health care providers. Increased services, support for primary care physicians who are typically responsible for those patients with chronic pain and, coordination of care between physicians and addiction services may have mitigated the effects of the crisis following the removal of OxyContin™. Public consultation and a critical evaluation of factors arising should be considered by those involved in planning and policy decisions for opioids in the future.In 2012, the narcotics monitoring system was implemented in concert with the increasing discourse on physician prescribing practices in the media and in the academic literature. The system was implemented as a surveillance tool to monitor physicians’ prescribing practices . With a In 2015, the Ontario government made a unilateral decision to reduce the urine drug screening billing fee as a way to mitigate the increasing costs of OAT provision in Ontario. This decision was convergent to the public discourse questioning the need for OAT and the rhetoric of physicians being financially driven to enter the practice of addiction medicine –46. The Sumners et al. highlight that the dynamics of ideology and discourse can impact research uptake for decision making. In Canada, there is a lack of consensus between actors and networks of actors from very different ideological and disciplinary backgrounds relating to harm reduction and more specifically OAT. For example, although methadone maintenance treatment is considered the standard of care for OUD, methadone is one of the most highly debated, regulated, and controlled interventions in addiction treatment and one of the most regulated in medicine . To presDespite the efforts, initiatives and policy changes implemented in the last decade, the negative societal impact of opioids continues. With the growing availability of powerful opioids—including fentanyl and carfentanil— the crisis is becoming more obvious .Although the burden of opioids on society is difficult to estimate, it is well known that the costs associated with OUD are extensive . The estIn the present time, there is increasing public awareness and interest around the issue of opioids. Strategies which steer away from the stigma of substance use and towards patient centered initiatives have become more common in recent years. The Ministry of Health and Long-Term Care in Ontario, has been increasing efforts to enhance patient centered care through initiatives such as the Patients First Action Plan, which was updated in 2015 . In respSome jurisdictions such as Switzerland and Vancouver, Canada have been especially successful at reframing ideas about substance use disorders and treatment. Switzerland was successful at reframing the issue of OUD in a different way. For example, such a change occurred when provision of needles to injecting drug users was reframed from a policy of drug maintenance to a policy of harm reduction for HIV . ChanginHere we demonstrated how attitudes and policy decisions are closely associated: when not aligned with evidence, policies can have unintended consequences. Vancouver and Switzerland are examples of how attitudes and patient centered planning, can influence policy decisions and entice people to come together which has the potential to create positive change. In Ontario, policies and ideological points of view are shifting into more preventative, holistic, patient centered models; however there continues to exist stigma, blame, and competing ideologies of addiction treatment. Despite efforts and evolving policies in Ontario, the missing piece to make policies actionable is the focus on aligning views and a critical evaluation of all factors impacting the issue rather than taking reactive action on the ever-evolving opioid crisis.We have outlined that narrative and discourse can have a significant impact on the way in which policies are prioritized . We beli


Rf identical with that of the standard. Such a match is a necessary but not a sufficient means of compound identification.The balanced capabilities of a high resolution separation method coupled with a flexible detection method such as mass spectrometry results in powerful analytical methods including gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. However, separations for diverse applications such as organic synthesis, pharmacological analysis, and biochemical separations are still based on static chromatography, defined as a method in which the separation of sample components is based on a spatial separation, rather than on a difference in retention times. Although capabilities for separation of very complex mixtures for static chromatography (thin layer or paper chromatography or electrophoresis) do not rival the very high resolution achievable with the gas and liquid chromatography, the resolution is adequate for a large number of applications, and the ease and low relative cost of the methods are advantageous. General detection methods for organic compounds separated by these forms of chromatography still seem relatively crude. Color development, charring, staining, or fluorescence measurements provide the location of sample spots, but little information about sample identity. In many cases, sample identity is suggested on the basis of an x and y axes into and out of the point of instrument focus, defined as the locus of the primary ion beam, and the secondary ion extraction optics of a quadrupole mass spectrometer. Data in four dimensions are generated: x, y, m/z ratio, and relative abundances of the ions in the mass spectrum [Over the past 2 years, we have constructed a secondary ion mass spectrometer (SIMS) that accommodates large chromatograms within the source, and sputters organic ions from the surfaces to produce the mass spectrum of samples directly from the chromatogram. Details of instrument construction have been reported . In essespectrum .Analytical advantages of the chromatography/SIMS instrument include an independent access order to sample spots, variable integration time for spectral measurement, variable spatial resolution adjusted in real time to maximize analysis efficiency, the ability to store sample as well as data generated in its analysis, preservation of all sample applied to the chromatogram, the ability to analyze chromatograms from outside sources, and the ability to calibrate the instrument with each chromatogram . We havem/z 357; similarly, the SIMS spectrum of cholic add contains an abundant ion at m/z 355. The mass spectral data acquired over the range of x and y coordinates is reconstructed for ions of these masses. These data were acquired with a cesium ion gun with moderate spatial resolution. The maximum sample spot diameter is 1 mm, and 5 μg of each compound were present in the spot. Spectra could be recorded for several hours in each analysis (sample consumption rate is a few tens of picograms per second), and the same distribution is recorded if the chromatogram is removed from the mass spectrometer, stored, and reanalyzed later.m/z 223. Variation of this particular ion with x and y is shown in the abundance plot. The same data are shown plotted as isoabundance contours. Each ion in the SIMS spectrum derived from the sample exhibits similar contours, and pattern recognition programs can be used to link such ions together to form a mass spectrum of the compound free of background.The chromatography/SIMS method has been extended to the indirect analysis of electrophoretograms. Although aqueous gels can be dried for analysis, this often degrades the spatial resolution of the separation and makes the gel difficult to handle. The high vapor pressure of water (even at low temperatures) precludes direct analysis of electrophoretic gels by SIMS. Standard sample transfer techniques such as Southern and Western blots are used to transfer samples to nitrocellulose and diazotized media, then analyzed by SIMS. Bradykinin and a series of related peptides have been so separated and analyzed; the SIMS spectra obtained are identical to those obtained from a discrete sample.Control of the physical and chemical nature of the chromatographic surface underlies the success of chromatography/SIMS. For maximum sensitivity, the sample should be in an ionic state, and should exhibit surfactant properties in the phase transition matrix used for the analysis . Figure


However, there are localised areas (11 districts) of high HIV transmission, described as hot spots, which include border districts, growth points, small-scale mining areas, fishing camps and commercial farming settlements.Zimbabwe was one of the sub-Saharan countries most severely affected by HIV and AIDS. The first AIDS case was reported in 1985. HIV prevalence increased sharply from 1985 to the mid-90s, peaking at 27.7% in 1997; thereafter, it started to decline .1 Accord1 New infections are estimated to be 69 105 and annual HIV deaths 63 853; 905 368 people are in of need antiretroviral therapy. Nearly 80.0% of adults have access to antiretroviral therapy, while only 40.5% of children have access to treatment.The number of people living with HIV in Zimbabwe is estimated to be 1 390 211, with an incidence of 0.98, for the 15–49-year age group .1 New inZimbabwe has a tiered laboratory network comprising three reference laboratories, five central hospital laboratories, eight provincial hospital laboratories and 66 district laboratories . AccordiEarly infant diagnosis (EID) is conducted at three sites, strategically located in different geographical locations to allow easier access to testing. The EID testing sites are in Harare at the National Microbiology Reference Laboratory, in the north of the country, Mpilo Central Hospital Laboratory in the south and Mutare Provincial Hospital Laboratory in the east. Health facilities send their EID samples to any one of the three laboratories, depending on their geographical location. Based on the number of HIV-positive mothers presenting at prevention of mother-to-child transmission screening that have accessed EID, Zimbabwe’s unmet EID needs are quite low.3 Zimbabwe is in the process of procuring eight viral load instruments – two bioMérieux NucliSENS® six Abbott m2000 instruments – through Global Fund. The Abbott instruments are due for delivery in October 2016. Partners such as the United States Agency for International Development have pledged to support human resources and other accessories. Zimbabwe has recently completed an evaluation of the Cepheid GeneXpert® viral load platform and the data are being analysed. They also evaluated the DRW Samba I platform, but there are reservations with this method and the country would like to evaluate Samba II.Zimbabwe has developed a national viral load scale-up plan in support of the 90-90-90 goals.Zimbabwe plans to roll out POC viral load testing at the district level in view of the complexity of the method and the increased workload on clinical health personnel at lower levels of the health system brought on by task shifting. It is envisaged that POC tests will provide access to viral load testing at low-volume sites in remote settings.Zimbabwe revised its laboratory’s strategic plan in October 2015 (unpublished), detailing the focus areas for laboratory services in Zimbabwe. The strategic plan will run until 2018.4 However, due to funding limitations, this is not yet been fully implemented. The Ministry of Health and Child Care has developed a policy on POC testing, which guides the selection, validation deployment and quality assurance for POC testing. This policy has yet to be approved and distributed.The Zimbabwe National Quality Assurance Programme (ZINQAP) is the national EQA provider. ZINQAP provides an accredited proficiency testing programme as well as training and mentorship in quality systems. ZINQAP provides its services to both public- and private-sector laboratories on a cost recovery basis. The ZINQAP EQA programme covers all the major disciplines of laboratory medicine, including microbiology, clinical chemistry, immunology, haematology and blood transfusion. On-site support and supervisory visits are conducted to assist poor performers to determine the cause of the poor performance and implement corrective and preventive actions. According to the Zimbabwe Medical Laboratory Guideline, medical laboratories are required to participate in a proficiency testing programme as a pre-requisite for registration.The EQA implementation models for HIV and related testing are as follows: EQA for HIV rapid testing is composed of proficiency testing panels prepared in-house by ZINQAP and distributed to participating sites on a monthly basis. However, less than 5% of sites are currently on the EQA programme, due to funding limitations. CD4 EQA for conventional CD4 analysers is also run by ZINQAP and is also composed of in-house prepared samples, which are distributed six times a year to participating sites. EQA for CD4 POC testing is prepared by QASI, an initiative of the Public Health Agency of Canada, which was previously distributed by the National Microbiology Reference Laboratory, before being transitioned to ZINQAP. There are 266 POC testing sites on the QASI POC CD4 EQA programme. The London School of Hygiene and Tropical Medicine is conducting a project in Zimbabwe to determine the cost of a national EQA system in collaboration with the Ministry of Health and ZINQAP. This project includes building capacity for ZINQAP to provide EQA to all POC CD4 sites . This mo6 EQA for POC testing is an important tool which can provide information on the quality of the whole POC testing process. The connectivity project being piloted in Zimbabwe, which includes a proof of concept for automated reporting of EQA results, presents a possible solution to the EQA challenge for POC testing. Automated connectivity solutions can be used to transmit EQA performance data to the EQA provider for data analysis, so that corrective action can be taken, if necessary, in a timely manner. This overcomes the current problem of a low percentage of sites reporting EQA results. Connectivity can also be perceived as being complementary to EQA, as it not only conveys information on test results but also operational data from the device, which can provide key equipment performance characteristics and quality indicators as part of a continuous quality assurance process. The system can also provide alerts when stocks are low, hence improving supply chain management.POC testing poses new challenges to EQA, especially taking into account that hundreds of devices are being deployed for use by non-skilled, non-laboratory personnel with limited knowledge of quality practices.The three EID sites participate in the EQA run by the National Institute for Communicable Diseases, South Africa. The viral load EQA programme is organised by the US Centers of Disease Control and Prevention, Atlanta; currently there is one laboratory site on this programme.Zimbabwe has been participating in EQA programmes since the mid-1980s. Proficiency testing services were obtained from the UKNEQAS, before the establishment of ZINQAP in 1998. Over the years, several lessons have been learnt regarding proficiency testing and EQA. An analysis of proficiency testing participation and performance records provides useful insights that can give guidance for policy makers and implementers. Local ownership of the programme is very important, as a home-grown programme is well versed in local challenges and best placed to come up with interventions to address challenges faced. A locally-coordinated programme also has the advantage of quicker turnaround times and can provide on-site support to poor performers. Local production of panels results in panels with characterisation that is similar to patient samples, which can best assess the testing systems.7 The national HIV response is based on testing; therefore, it is of critical importance to have a system of monitoring the quality of testing. It is important to ensure that there is adequate funding for the initiation and maintenance of the EQA programme. Initial establishment of the EQA programme can be through partner support, however, it is important to ensure the future sustainability and maintenance of the programme with financial support from its beneficiaries. Depending only on partner funding is not sustainable and poses the risk of collapse of the programme when funding is no longer available. It is also very important to have a mechanism that enforces EQA participation, with consequences for sites that do not participate. Clear understanding and appreciation of the value of EQA is critical to sustainability – it is important to establish a culture of quality.Financing of EQA programmes is of critical importance, as they provide important information on the quality of testing and therefore the reliability of the results obtained.8 There should be a system of validation and/or verification of test methods, equipment and devices before they are put into use. Policies, standard operating procedures and job aides need to be in place to provide the necessary guidance. Training and competency assessments of the personnel conducting the testing are necessary to ensure that tests are carried out correctly and the results obtained are accurate and reliable. An internal quality control system must be in place and documented. A supply chain management system to ensure uninterrupted service delivery is also important. There is also a need to have a proficiency testing programme to independently assess the quality of testing. In addition, it is necessary to have a system to provide on-site support and supervision to poor performers, including root cause analysis, corrective and preventive actions. All testing sites must participate in the programme. A locally-coordinated or run proficiency testing programme is of greater value, as it provides samples that are similar to patient samples. Funding and sustainability of the programme are of critical importance.A national quality assurance programme for HIV POC testing should provide clear guidance on selection and deployment of test equipment and methods.Billions of dollars are spent globally on test equipment, reagents and consumables for HIV. The HIV response is based on results obtained from various testing systems and it is thus of critical importance to ensure that there is a system of assessing and confirming that the tests conducted are accurate and reliable, so as to ensure quality patient care and efficient utilisation of resources.