Most often the newspapers and bulletin come out with voluminous cases of deaths due to drowning. At the same time an ample section of such cases encompass entomological evidences, that can be scrutinized as a very useful parameter in estimating post mortem interval (PMI). This research database is an outcome of a 2 years reflective study, based on an assessment of records related to human deaths due to drowning. The drowned bodies from various districts of Haryana are sent to PGIMS , Rohtak. The study took the data of year 2015–2016 into consideration. All the cases were reviewed and summarized in terms of monthly occurrence of total cases, age differentiation, gender differentiation and month wise occurrence of entomological evidences on the dead bodies through detailed study of post mortem findings. This data will lead to an insight into the magnitude of drowning deaths in Haryana along with the usage of entomological data for determining Post Mortem Submersion Intervals (PMSI). Specifications TableValue of the data•Routine monitoring of deaths due to drowning in an aquatic environment is very important for medicolegal and forensic purposes around the world.•Little is known about the trend of drowning related death in an aquatic habitat with respect to entomological evidence, so the present data emerge of immense value since no data is available on this important aspect from Haryana.•The information provided in this data set bring about new ideas for forensic experts and police officers about the trend of drowning deaths in an aquatic habitat with respect to the presence or absence of any entomological testament.•This kind of data is also useful for scientists and researchers working in the field of forensic medicine, aquatic entomology and forensic entomology. It administers detailing to the inhabitance of entomological specimen in this particular area.•Entomological facts generated in the study provide a pandora of information which can be useful for future efforts in the discipline of forensic entomology.•The details contributed here would be the first of its kind for the readers to fully understand the types and trends of drowning deaths with a special emphasis on entomological knowledge in an aquatic environment.•The present data shows the presence of entomological specimen with most of the recovered drowned bodies. The neglect of this evidence is no more possible.•This data will also provide means of determining PMI in aquatic environments, when the initial signs of decomposition have passed off.•This data serves as a source of information for the research institutes as well as for the forensic science community. It can be further used to correlate the significance of entomological specimen present in drowned bodies for future research in this particular area.1The data provided in this article explain about the trend of deaths in an aquatic environment and the significance of entomological evidence in drowning deaths from Haryana, India . There h2Experimental design consists of frequencies based on the distribution patterns of death due to drowning in an aquatic system. These patterns were evaluated in the context of location, year, month, gender and age wise variations. The present database comprises of drowning death cases reported in the Department of Forensic Medicine, Post Graduate Institute of Medical Sciences (PGIMS), Rohtak from 1st January, 2015 up to 31st December, 2016. All the drowning related death cases were surveyed and filtered from the Post-mortem Reports (PMRs) , Table 5


Action research (AR) has an important role to play in educating physical therapists. Increasing efforts should be encouraged to instigate AR programs in physical therapy practice and clinical education. Such programs commonly require considerable effort and understanding by clinical instructors, and require adoption of new educational methods. AR programs can lead physical therapists and clinicians to be more questioning and reflective in evaluating practical questions regarding patient therapy and education. The purpose of this article is to educate the readers on the importance of AR and to provide a few relevant references on that topic. A specific study is described in this paper in which physical therapy clinical instructors participated in a structured workshop designed to demonstrate the values of AR and how such values can be incorporated in teaching their students. AR can lead to improved therapist-patient interaction and help solve specific practical problems arising during therapy sessions.


For genomic medicine research to be fully translated into clinical care, it is critical for researchers to engage stakeholders who ultimately regulate the use of genomic technologies and therapeutics within healthcare practice. Herein, we describe an example of how this might work. Notwithstanding the historical hype of genomic medicine , there iProducing the evidence is but the first step toward implementation of genomic medicine. Efforts to engage with target communities and patient stakeholders are now a frequent component of clinical genomics research protocols . Successhttps://cser-consortium.org/), Implementing Genomics in Practice , and Clinical Genome Resource . A primary aim of these public-funded projects is to elucidate whether and how genomic technologies can be utilized to improve patient outcomes and optimize healthcare for the population and individual. In other words, much of research is focused on the analytic and clinical validity as well as clinical utility of genomic technologies. Researchers’ definitions of these concepts may vary considerably from that of regulatory groups, however. Rather than producing scientific evidence with the assumption that it will meet the evidence requirements for policy development, it is important to engage individuals making both coverage and regulatory decisions to understand the evidence needs and assessment processes of these stakeholders. Such engagement may facilitate understanding between researchers and regulators and help ensure study designs and outcomes achieve their intended goals.Currently, many of the research programs producing the growing body of evidence for healthcare applications of genomic medicine are associated with or directly linked through large-scale consortia funded by the National Human Genome Research Institute (NHGRI), under the purview of the National Institutes of Health (NIH). Examples include Clinical Sequencing Exploratory Research  in genomic medicine and their evidence/data needs for policy development and decision-making. Key questions may include the following: (1) What is each regulatory group’s role(s) in genomic medicine and how can research efforts contribute to their specific aims? (2) What types of evidence are needed to support each group’s regulatory decisions? (3) Do the research aims align with the evidentiary needs and/or can the study protocol be amended in response to the required data/evidence? (4) Are there mutual benefits to establishing a relationship? (5) Is it feasible to build and sustain a relationship of transparency, communication, and dissemination?The US Food and Drug Administration (FDA) proactively expressed interest in ClinGen’s approach to curation of genes and variants. Based on this interest, ClinGen sought to establish a process of engagement with the FDA as the first stakeholder. The interactions to date between ClinGen researchers and the FDA described here are presented as an example of how such engagement could work. To facilitate the development of this stakeholder relationship, a small workgroup of key program contacts/liaisons from the relevant organizations  met monthly via conference calls. At the outset, roles and interests were defined as summarized in Fig. The open dialogue generated by establishing this relationship has provided a means through which to clarify and/or contextualize confusing or misunderstood jargon and concepts in terms of the research and the regulatory processes. Acknowledging the need for shared learning is essential to building a mutually respectful relationship. The formal development of a dedicated liaison and workgroup tasked with engaging regulatory groups has allowed broader contextualization of overarching goals and minimized the possibility for ambiguous messages or distorted perceptions.The relationship has allowed ClinGen researchers to understand the potential uses of ClinGen resources for FDA regulatory purposes and to align curation processes to produce a resource consistent with FDA draft guidelines on regulatory-grade databases . The accThrough this experience, it has become evident that engaging with regulatory stakeholders, such as the FDA, can not only be helpful in the development of the ClinGen resource, but is essential to guiding appropriate utilization of the generated evidence to support improved health through genomic medicine Fig. . This exThe need for continued and increased regulatory engagement activities among genomic medicine research is great, and the potential impact of these types of interactions to further clinical genomic medicine may be well worth the effort.


Sickness absence rates in the UK continue to exceed those in much of the developed world, with an annual cost to employers of £29 billion. Rates of sickness absence in the public sector are higher than those in the private sector, with the exception of the fire service where they are consistently lower.To understand the influences that increase attendance among operational firefighters.A series of semi-structured interviews undertaken with operational staff to explore their attitudes to sickness absence.Review and analysis of participant responses identified a number of key themes, namely employee well-being, including physical fitness and mental health; employee engagement with the fire service as manifested by culture, experience, nature of the job and leadership; organizational factors including the staffing model and relationship with occupational health services and policy, which describes both refinements to and implementation of targeted policies.Previously observed factors such as improved fitness and the distinct firefighter culture play a role, yet other factors emerged that could explain the differences. These include the greater work–life balance offered by their shift patterns, the terms and conditions of employment and perhaps most importantly the evolution of precisely targeted policies that understand the unique nature of the operational fire service. The rates of sickness absence in the UK, where workers take an average of 9.1 sick days per year, costing employers around £29 billion in sick pay and employees £4 billion in lost earnings  and a nuAt first glance, these figures may appear incongruous considering the hazardous nature of operational firefighting and the risk of physical injury and exposure to psychological stress ,9. TheseThe study took place within WMFS, the second largest UK Fire and Rescue Service (UKFRS) and one that provides emergency services to 2.7 million residents of the seven local authorities within the West Midlands metropolitan county. The workforce consists of some 1500 operational and 500 non-operational staff. Operational staff are made up of firefighters or fire officers, organized into groups known as ‘watches’, working either day or night shifts typically in a pattern of 4 days on and 4 days off. Non-operational staff work in fire control and are responsible for handling emergency calls to the service, with shift patterns similar to operational staff, or in specialist and administrative roles such as human resources or finance where staff typically work more conventional office hours.All those invited to participate in the study were operational staff directly employed by WMFS and purposively sampled to reflect a range of rank, gender and length of service. The intention was not to sample proportionate numbers of each rank but instead for our sample to incorporate maximum variance, i.e. to reflect the range of seniority of operational employees. Written invitations were issued to all six operational watches from occupational health. Semi-structured interviews by the second author, a member of the occupational health unit at WMFS, were used to capture individual experiences of operational staff regarding their motivation to attend and the factors that influence this motivation. These include attitudes to their role and to their colleagues and the current management of sickness absence within the service . CollectWhat emphasis do you place on the importance of physical health?What emphasis do you place on mental health?Are there any aspects of your role that encourage you or your colleagues to attend work?Are there any aspects of your work environment that encourage you or your colleagues to attend work?Are there any aspects of the way your work is organized that encourage you or your colleagues to attend work?What impact if any have management policies had on whether you or your colleagues attend work?A total of 16 interviews were conducted with staff who had served between 8 and 28 years and ranged in rank from station commander to firefighter. The response rate was low at 24%, although the requisite job titles and watches were represented in the group interviewed. Only two of the participants were female which though small is indicative of the lower numbers of female operational staff. The characteristics of those interviewed are summarized in The first theme of ‘employee health’ describes the attitudes of operational staff to physical fitness and mental health. This included how they related to exercise and their attitudes to mental health and the reluctance to use the word stress. Quotations illustrating these findings are contained in The second theme was ‘employee engagement’ which describes the connection staff felt with their colleagues and their organization . It appeThe third theme identified, ‘organizational factors’ describes the structure of the organization and how resources are utilized . SpecifiFinancial incentives were also described and reference made to the continuing professional development (CPD) payment of up to £900 per annum available to operational individuals as part of their National Joint Council terms and conditions of employment. This payment can be withheld if sickness absence exceeds stated limits (quotation 18). However, potential drawbacks in the form of presenteeism were also recognized as one consequence of using these financial rewards (quotation 19). Whatever the policy, there was an understanding that they were only successful if implemented correctly and the importance of raising awareness in senior staff of the content of the policy and how it should be executed was noted (quotation 20).A number of potential influences on attendance among operational fire service staff emerged. These included the physical and mental resilience borne of their training and the engagement that comes from the distinct role and culture of the fire fighter. However, there appeared other important factors such as the shift system that provides a better work–life balance and changes to policy that helped reduce the sense of entitlement to sick pay, encouraged responsibility for attendance and introduced the potential for financial penalties. We present what are to our knowledge the first detailed insights into the factors that underlie the low sickness absence rate of these public sector employees. Staff with a range of experience and rank were interviewed, reflecting the broader operational workforce. We further point out the advantages of an interviewer within the same organization, a role as occupational health advisor providing both understanding of the organization and trust within it, both of which are recommended characteristics when gathering qualitative data . That saPreviously research has shown how improved physical fitness can help reduce sickness absence  and the Engaged employees take less sickness absence  and charThe impact of correctly implementing a precisely worded attendance management policy has long been recognized and a number of successful policy adjustments were described by our participants. These included more robust policies to reduce the sense of entitlement and the requirement of colleagues to cover for absent team members, potentially a persuasive factor when considering the camaraderie of firefighter culture. One further policy change that appeared effective, though not without prompting concerns of presenteeism, was linking continual professional development payments to attendance. Previous research has also described the positive impact of financial incentives on work attendance  particulOur study has identified a number of factors that appear to contribute to continued low levels of sickness absence observed in the operational fire service. Future work might attempt to quantify some of our findings and determine further their relative importance both alone and in combination. Our qualitative work now needs underpinning with quantitative data to help determine which interventions and occupational settings would be most effective. A starting point would be to pilot interventions based on the influences we have identified in isolation across non-operational staff groups within the fire service and begin to build an evidence base of demonstrable efficacy.This is the first study of its kind to try to identify and understand the factors determining why sickness absence rates observed among operational firefighters are the lowest in the public sector.Though physical fitness and firefighter culture play a part, other factors came to light including the positive work–life balance afforded by fire service shift patterns and the evolution of precisely targeted policies that understand the unique nature of the operational fire service.The relative importance of the factors identified and how they combine should be explored further in view of the potential benefits of reducing sickness absence in other groups of public sector workers.P.H. was employed directly by WMFS as a senior occupational health advisor. I.L. declares no conflicts of interest. The findings and conclusions in this work are those of the authors and do not necessarily represent the official position of WMFS.


Cytotoxic chemotherapy brings routine cures to only a small select group of metastatic malignancies comprising gestational trophoblast tumours, germ cell tumours, acute leukemia, Hodgkin’s disease, high grade lymphomas and some of the rare childhood malignancies.We have previously postulated that the extreme sensitivity to chemotherapy for these malignancies is linked to the on-going high levels of apoptotic sensitivity that is naturally linked with the unique genetic events of nuclear fusion, meiosis, VDJ recombination, somatic hypermutation, and gastrulation that have occurred within the cells of origin of these malignancies.In this review we will examine the cancer stem cell/cancer cell relationship of each of the chemotherapy curable malignancies and how this relationship impacts on the resultant biology and pro-apoptotic sensitivity of the varying cancer cell types.In contrast to the common epithelial cancers, in each of the chemotherapy curable malignancies there are no conventional hierarchical cancer stem cells. However cells with cancer stem like qualities can arise stochastically from within the general tumour cell population. These stochastic stem cells acquire a degree of resistance to DNA damaging agents but also retain much of the key characteristics of the cancer cells from which they develop. We would argue that the balance between the acquired resistance of the stochastic cancer stem cell and the inherent chemotherapy sensitivity of parent tumour cell determines the overall chemotherapy curability of each diagnosis.The cancer stem cells in the chemotherapy curable malignancies appear to have two key biological differences from those of the more common chemotherapy incurable malignancies. The first difference is that the conventional hierarchical pattern of cancer stem cells is absent in each of the chemotherapy curable malignancies.The other key difference, we suggest, is that the stochastic stem cells in the chemotherapy curable malignancies take on a significant aspect of the biological characteristics of their parent cancer cells. This action includes for the chemotherapy curable malignancies the heightened pro-apoptotic sensitivity linked to their respective associated unique genetic events.For the chemotherapy curable malignancies the combination of the relationship of their cancer stem cells combined with the extreme inherent sensitivity to induction of apoptosis from DNA damaging agents plays a key role in determining their overall curability with chemotherapy. Despite the introduction of a significant number of new cancer therapeutics that target specific molecular pathways within malignant cells, the use of DNA damaging cytotoxic chemotherapy currently remains the mainstay in the management of most malignancies .In the majority of metastatic malignancies, DNA damaging cytotoxic chemotherapy can reduce the disease bulk, improve symptoms and extend life . HoweverBeginning in the 1950s and fully established by the 1980s there has been the development of routine curative chemotherapy treatment for most patients with acute leukemia, high grade non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, testicular and ovarian germ cell tumors, the gestational trophoblast tumors and for many cases of the rare childhood malignancies , 4. In cThere is clearly a significant clinical and biological divide between these rarer malignancies that can be routinely cured with cytotoxic chemotherapy and the majority of the more common cancers that are incurable in the metastatic setting and only relatively rarely cured even in the adjuvant setting. The biological explanation for this divergence presents a significant challenge to both understating of the cellular processes involved and to the development of more effective approaches to care , 7.With such a routine but dramatic and reproducible divide in chemotherapy sensitivity and treatment outcomes between these differing tumor cell types, the conventional explanations that ascribe chemotherapy resistance to the two main continuous variable parameters of the rate of tumour cell growth and the development of genetic mutations that lead to resistance are perhaps worthy of an updated review.Historically the concept of the inherent chemotherapy sensitivity of tumour cells and the concept of ‘log kill’ originated in early models that used murine leukemia as the model , 9. As wWe have recently suggested an alternate biological explanation for the extreme chemotherapy sensitivity of the chemotherapy curable malignancies. The theory centres on the close association between the cells of the chemotherapy curable malignancies and the occurrence of their unique genetic events of nuclear fusion, meiosis, variable-diversity-joining (VDJ) recombination, and somatic hypermutation (SHM) each of which has naturally upregulated apoptotic pathways as shown in Table th century [The existence and important role of cancer stem cells appears to support many of the clinical observations on malignant cells and their responses to treatment. Whilst their existence was originally suggested in the 19 century , cancer  century , 12. Fur century –17. Over century .The importance of tissue specific somatic stem cells on cancer biology and therapeutics is twofold. Firstly, the existence of tissue specific stem cells allows for cells to be sufficiently long lived to be able to accumulate the number of mutations required to develop the malignant phenotype . The secThe resistance to chemotherapy of the normal tissue specific somatic stem cells appears to be routinely shared by the stem cells that have undergone malignant transformation and have become cancer stem cells . It is bThe main cancer stem cell model relates to cancer stem cells that form a hierarchy in giving rise to the tumour cells, following the linear progression from somatic stem cell to cancer stem cell and then to cancer cell. However there is also evidence that cells with some similar properties of stemness can arise from within the tumour cell pool in the stochastic cancer stem cell model. However these cancer stem cells having a different aetiology to hierarchical stem cells and the potential to have different biological characteristics. These two approaches to cancer stem cells are not mutually exclusive with stochastic cancer stem cells being reported in colon cancer that is also supported by a hierarchical cancer stem system .By definition the development of the malignant phenotype dramatically affects the biology of the cell with a major impact on the inhibition of normal patterns of cellular differentiation, senescence, ageing and programmed cell death . The resThe most dramatic impact of the onset of the malignant phenotype on altering cellular development can be seen in B and T cell malignancies which arise at a number of differing points along the normal but complex linear lymphocyte development pathways. In these malignancies, the malignant cells appear to become developmentally frozen with no further progression in the normal inear development of these cells from the time of the onset of the malignant phenotype . As a reMore recently we have postulated how the impact of the onset of malignancy on freezing the cells normal developmental progression may leave malignant cells developing at certain normally transient but key developmental points with fixed heightened physiological pro-apoptotic potential . For eacAlongside the major contribution made to chemotherapy responses of the chemotherapy curable malignancies by the apoptotic sensitivity associated with their associated unique genetic developments, the ABC transport proteins also plays an important role in determining chemotherapy responses , 29.A number of studies have indicated that the expression of this family of molecules is associated with a reduction in the efficacy of chemotherapy as a result of the increased efflux of drugs from cancer cells , 31. HowThe relationship between stem cells, the cancer cell of origin, the expression of the ABC system and the response to chemotherapy treatment in the chemotherapy curable malignancies helps to define the unique biology of these cells.The ABC protein system is widely expressed in conventional tissue specific stem cells, where it plays a key role in protecting these cells from genotoxic stress . SimilarHowever, as previously discussed, in the chemotherapy curable malignancies, there are no standard hierarchical cancer stem cells derived from the tissue specific stem cells and each of these malignancies arises from a transient developmental cell. It is apparent that these transient developmental cells have very differing patterns of ABC protein expression compared to tissue specific stem cells and this status appears to impact significantly on the expression of ABC proteins in malignancies derived from them.In normal trophoblast cells, assessment of the expression and functional activity of ABC transporter genes in murine embryos indicate that activity of these efflux systems is not present immediately post nuclear fusion but only becomes active by day 6 . PatholoThere is less data on the expression of the ABC family proteins in choriocarcinoma and placental site trophoblast tumours, however the limited data indicates that the majority of cases of choriocarcinoma or PSTT do not express ABCB5 .B and T cell malignancies arise from differing transient cell types occurring along the lymphocyte development pathways . The levData suggests that this variation in ABC protein activity during normal B cell development is reflected in the various malignancies arising along the course of lymphocyte development. A number of studies have indicated that there the expression of ABC family members is significantly lower in both B cell and T cell ALL than in HSCs . This reIn Hodgkin’s lymphoma which is believed to arise from germinal centre B cells, the majority of cases do not express ABC proteins. Of note a more recent study has indicated that the approximately 30% of Hodgkin’s cases that do express the ABCC1 protein have a tendency to a worse prognosis . SimilarIn contrast in CLL, levels of ABC proteins are higher than in DLBCL  and myelIn testicular cancer characteristically the majority of ABC proteins are expressed at only very low levels, with significant levels of expression only seen in tumours that have demonstrated chemotherapy resistance . The preReviewing the chemotherapy curable malignancies as a group it is apparent that they have this additional shared characteristic of generally low levels of ABC protein expression. This finding is intrinsically linked to particular cells of origin of these malignancies being transient developmental cells. Each of these developmental cells themselves have low ABC expression, rather than the high levels that are seen in hierarchical cancer stem cells. The relative role that these low levels of ABC expression plays compared to the impact of the unregulated apoptotic pathways associated with the unique genetic events occurring in these cells is an area to debate and hopefully one with interesting data to come.In the common epithelial malignancies the conventional structure of the cancer stem cell is the hierarchical system as shown in Fig. In contrast in the chemotherapy curable malignancies the role and relationship of potential cancer stem cells appears to be significantly different in both the hierarchy of the cancer stem cell/cancer cell relationship and also of crucial importance in the characteristics of the cancer stem cell with regards to sensitivity to chemotherapy. Cancer stem cells in the chemotherapy curable malignancies have proven to be challenging to study but cells with stem like properties have been reported in most of these diagnoses. As discussed below it appears that in each case of the chemotherapy curable malignancies they do not have standard hierarchical cancer stem cell structure, however they do have a population of cells that have developed cancer stem cell qualities when arising from the malignant cells themselves in a stochastic or non-hierarchical model.The origin of the cancer stem cells in these malignancies may have a dramatic impact on their characteristics. Whilst the hierarchical stem cells will share many characteristics with the tissue specific somatic stem cells from which they arise, the stochastic stem cells arising from within the cancer cell pool whilst taking on some of the acquired characteristics of stemness, will also take on some of the primary biological properties of the malignant cell . We woulALL characteristically arises in pro-B cells that have or are undergoing VDJ recombination of their immunoglobulin genes . B cellsResearch into the existence and potential characteristics of cancer stem cells in acute lymphocytic leukemia (ALL) has been an area of considerable endeavour. A number of studies have indicated that there is no cancer stem cell hierarchy in ALL , 55, 56 Lymphoma presents a range of diagnoses of B cell malignancies arising from mature B cells that have completed VDJ recombination. Cells with stem like properties have been identified in a number of types of mature B cell malignancies including chronic lymphocytic leukemia (CLL), follicular lymphoma and myeloma –60. In kWe have previously hypothesised that the relationship to the onset of malignancy and the relationship with the VDJ or SHM activity determines much of the sensitivity of the malignant cells to chemotherapy and would argue that this degree of sensitivity is maintained in the stochastic cancer stem cells arising from these malignancies. The malignancies closely linked to VDJ and SHM, ALL, DLBCL, Hodgkin’s disease and Burkitt’s lymphoma are routinely curable with chemotherapy. However in contrast in malignancies arising distant from these genetic events; CLL, mantle cell lymphoma and multiple myeloma are not chemotherapy curable. We would argue that the apoptotic sensitivity linked to VDJ and SHM is absent in these cells distant from these events so determining the lack of extreme chemotherapy sensitivity in both the malignant cells and their counterpart stochastic stem cells.The pregnancy associated malignancies of post molar pregnancy trophoblast tumour and gestational choriocarcinoma are rare but highly curable with chemotherapy treatment , 63. TheGerm cell tumours are rare and predominantly arise from the pre-malignant precursors carcinoma in situ (CIS) in men and gonadoblastoma in women , 66. BotThe childhood malignancies have less clear developmental pathways but are generally believed to arise from embryological cells with blocked and failed development. We have previously postulated that the high apoptotic potential and chemotherapy curability of these rare malignancies is linked to the development of the malignant phenotype and blocked development occurring soon after gastrulation .In neuroblastoma the malignant cells are primitive cells with blocked embryological development that prevents normal cellular differentiation . Cells wThe finding that these other potentially chemotherapy curable malignancies do not arise in the conventional hierarchical manner from cancer stem cells related to standard tissue specific stem cells, also helps explain why these tumours frequently do not relapse after successful chemotherapy treatment.In the chemotherapy curable malignancies, the cells of each diagnosis arise from a cell which would normally have a transient passage through a complex developmental stage during which they become malignant. In health, a normal cell does not persist long term as a new trophoblast cell, or as a pro-B cell or germinal centre B cell, similarly the process of meiosis occupies only a relatively brief step in the complete pathway of production of sperm from sperm stem cells. In health cells passing through these developmental stages, do so for a relatively short length of time, and then exit to either the next stage in their development after their unique genetic event successfully occurs or naturally undergo apoptosis in response to event related DNA damage or an absence of positive selection.In the common solid malignancies the hierarchical relationship of the tissue specific somatic stem cell, the cancer stem cell and the cancer cells is relatively simple with the tissue specific stem cell giving rise through mutation to the cancer stem cell and the cancer stem cells in turn giving rise to the more rapidly growing standard cancer cells .In contrast in the chemotherapy curable malignancies the relationship and role of cancer stem cells is more complex and at present less clearly defined. The biological difference is most easily seen in the B cell and T cell malignancies where there is a very differing relationship with their stem cells than most conventional malignant cells. Here the stem cell that is the original source of cells for all lymphoid and myeloid malignancies is the haematopoietic stem cell (HSC). However this cell, which is very resistant to chemotherapy, only acts in the conventional stem situation for the initial lead off into B cell, T cell and myeloid cell development. After this point the B cell and T cells undergo the complex genetic recombinations of V(D)J genes and for the B cells somatic hypermutation and class switching that lead to their specific clonal identity. These processes in which DNA is cut, rearranged, mutated, rejoined and repaired contain much of the risk of DNA damage that leads to leukamagenesis and lymphomagenesis  but alsoThe malignancies that arise further along these pathways and more distant from the HSC are physiologically very different cells and now clonally and mutationally only very distantly related to the original HSC. Whilst HSC that carry mutations have been recognised to confirm a risk of development of CLL, these cells are not directly clonally related to a current diagnosis of CLL and cannot serve to repopulate the pool of established CLL cells after chemotherapy treatment . Whilst In a similar fashion there is a similar lack of conventional hierarchical cancer stem cells for the other chemotherapy curable malignancies. In the gestational tumours the malignant cells arise from the primitive trophoblast cells, which are present for only short time after conception and nuclear fusion. Similarly the malignant germ cell tumours have no healthy counterpart and are believed to arise from arrested gonocytes that having ongoing meiosis/mitosis stresses. These cells are not present in health and the malignant germ cell tumour cells are not supported by stem cells arising from the spematogonial stem cells.These biological observations suggests that the chemotherapy curable malignancies share a common theme in that they do not have conventional hierarchical cancer stem cells. In each case their cancer stem cells appear to arise either from within the cancer cell pool in the stochastic model, as in ALL, lymphoma and choriocarcinoma, or from a persistent embryonal cell with blocked development as in the childhood malignancies and germ cell tumours. In Table This observational model on the relationship between the chemotherapy curability of cancer cells and their stem cells is complicated in that some types of B cell and T cell malignancies including CLL, follicular NHL, multiple myeloma and the mature T cell malignancies also will share the same non-hierarchical stem cell model, frequently respond well to chemotherapy treatment but are not curable with chemotherapy.In this situation we would argue that the characteristics of the stochastic stem cells with regard to DNA damage and induction of apoptosis is not determined solely by the process of their development of stem cell characteristics but is also very significantly affected by the intrinsic characteristics of the malignant cell from which they arise . Figure The ability of simple cytotoxic DNA damaging chemotherapy drugs used as single agents or more commonly in combination to cure a select group of relatively rare malignancies has been one of the great achievements from the early days of cancer therapeutics in the 1950–70s. However since then, despite enormous endeavour, no additional metastatic malignancy has been added to the short list of routinely curable metastatic cancers.This dramatic divergence in responsiveness between different malignancies to chemotherapy treatment and how to improve it, has been one of the major areas of oncology research. In this paper we have reviewed how the cancer stem cell structure associated with these malignancies may impact on this divergence.Our observations indicate that each of the chemotherapy curable malignancies arise in a cell type that has a transient passage through a complex developmental stage involving complex DNA manipulation. The conventional hierarchical cancer stem cell system is absent in each of the chemotherapy curable malignancies and these factors are likely to be an important associations with the dramatic and divergent responses seen to chemotherapy. Additionally each of the chemotherapy curable cancers arises from a parent cell that has much lower levels of ABC transporter protein expression than hierarchical cancer stem cells have is also likely to lead to a further increase in efficacy of chemotherapy treatment.In the chemotherapy curable malignancies the cancer stem cells where present, generally arise in a non-hierarchical or stochastic method from within the pool of tumour cells itself. In each malignancy these cells are either developmentally isolated from their originating tissue specific somatic stem cells or have no conventional hierarchical cancer stem cells. As a result of the absence of a hierarchical cancer stem cells, the chemotherapy curable malignancies can only have cells with stem cell like properties that have arisen from with the cancer cell pool. These cells will take much of their properties from the cancer cells rather than having the propertices of a conventional cancer stem cell that is closely related to the damage and chemotherapy resistant somatic stem cells.We have previously postulated the potential importance regarding the presence of the key cellular pro-apoptotic sensitivity associated with the unique genetic events of nuclear fusion, VDJ recombination, somatic hypermutation, meiosis and gastrulation. Normal healthy cells undergoing these activities are exceptionally sensitive to the action of chemotherapy drugs, as seen in the action of methotrexate in producing pregnancy loss , of chemWe would argue that this association also directly impacts on the chemotherapy sensitivity of the non-hierarchical or stochastic cancer stem cells associated with these varied malignancies. In this situation the responsiveness to chemotherapy of the stochastic cancer stem cell will be determined by both the acquired characteristics of stemness but also significantly impacted by the underlying apoptotic sensitivity of the malignant cell. As a result, in the chemotherapy curable malignancies the degree of chemotherapy resistance that the adoption of stemness gives to these stochastic cancer stem cells, is functionally outweighed by the apoptotic sensitivity and allows the chemotherapy to kill the stem cells. In contrast in the similar malignancies of CLL/mantle cell lymphoma/myeloma/low grade NHL which also have stochastic stem cells and no hierarchical stem cells, their stochastic stem cells do not have this extreme apoptotic sensitivity and their stem cells are able to survive the chemotherapy, in a similar fashion to standard hierarchical cancer stem cells.In this debate section, it is clear that there is a great deal of data needed to confirm or repudiate this new hypothesis. To date there has been only limited research on these natural apoptotic pathways, their mechanisms and the controls occurring in these cells. Additionally there has been also limited work on the differential apoptotic responses of the chemotherapy curable malignancies compared with the incurable. However whilst this paper may serve as a prompt to explore these areas in more depth it should also serve to remind that the genes that can give rise to overwhelming apoptosis in response to chemotherapy are present in every cancer cell and in their respective cancer stem cell. The key of how to unlock this potential is awaited.


Since the signing of the Oslo Ministerial Declaration in 2007, the idea that foreign policy formulation should include health considerations has gained traction on the United Nations agenda as evidenced by annual General Assembly resolutions on global health and foreign policy. The adoption of national policies on global health (NPGH) is one way that some member states integrate health and foreign policymaking. This paper explores what these policies intend to do and how countries plan to do it.White Paper on Global health in foreign and development policy and the Swiss Health Foreign Policy using Schneider and Ingram's policy design framework. After replicating analysis methods for each document, we analysed them side by side to explore the commonalities and differences across elements of NPGH design.Using a most similar systems design, we carried out a comparative study of two policy documents formally adopted in 2012. We conducted a directed qualitative content analysis of the Norwegian Analyses indicate that NPGH expect to influence change outside their borders. Targeting the international level, they aim to affect policy venues, multilateral partnerships and international institutions. Instruments for supporting desired changes are primarily those of health diplomacy, proposed as a tool for negotiating interests and objectives for global health between multiple sectors, used internally in Switzerland and externally in Norway.Findings suggest that NPGH designs contribute to constructing the global health governance system by identifying it as a policy target, and policy instruments may elude the health sector actors unless implementation rules explicitly include them. Research should explore how future NPGH designs may construct different kinds of targets as politicised groups of actors on which national governments seek to exercise influence for global health decision-making. The adoption of global health strategies by some governments in European countries over the past decade represents a formalised approach to health and foreign policymaking at the national level.Case studies on the development of the UK's and Germany's global health strategies have contributed to understanding the motivations and interests for their production in those countries.Little is known about the content of these documents regarding what they propose to do from a public policy perspective.Actors at the international level that make policy are targets for countries to influence change related to global health;Health diplomacy is an instrument countries use either domestically or internationally for supporting the desired change related to global health;The specification of rules for implementing NPGH varies between these policy documents.Based on a comparative analysis of formally adopted national policy on global health (NPGH) documents in Norway and Switzerland:Actors in the global health governance system are the target population intended to benefit from change as a result of implementing NPGH.When policy instruments are unfamiliar to or outside of the mandate of actors in the health sector, the implementation of NPGH may exclude structures from the health sector unless rules specifically include them.An empirically informed definition of NPGH is proposed for researchers and policymakers.The Oslo Ministerial DeclarationWe define NPGH as policies that aim to organise and co-ordinate a state's action on global health across more than one sector of public administration, as part of a coherent approach to policy development and implementation between relevant ministries involved in improving health on a global scale.24By questioning what NPGH intends to change and how it plans to accomplish this, we aim to better understand the multilevel and multisectoral empirical characteristics of such policies. First, NPGH requires domestic actors to collaborate to improve health globally, but it remains unspecified where change is expected . Second, NPGH demands that the health sector collaborates with the foreign affairs and the development sectors, but we do not know whether the goals and methods of intervention will be those of the health sector or of another sector. To this end, we study NPGH with tools of health political science, a field of research that uses theories from political science in health policy research to generate knowledge about policy change in matters related to public health.25In policy science, policy design is generally conceptualised either procedurally  or substantively .We conducted a comparative study of the content in cases of NPGH policy design from two countries. In this study, we define a case of NPGH policy design as a formally adopted policy document at the highest level of government.Using three criteria , we selected cases of NPGH policy design adopted in 2012 by Norway and Switzerland from a group of four countries in Europe who have adopted such policies.In line with other studies on health and foreign policies that identify a single policy document as a country's policy framework for its national global health strategy,We manually coded text of the two policy documents using Schneider and Ingram's six elements of policy designWhite Paper on Global health in foreign and development policySwiss Health Foreign PolicyNorway's The Norwegian and Swiss policies aim to act on the global health governance system by influencing change in policy venues, international institutions, networks and partnership structures where decisions about global health policy and programmes are made. The main targets for the Norwegian policy are international policymaking arenas where political and economic support are mobilised for global health such as United Nations agencies ), the World Bank, Global Health Initiatives (GHI) , Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM)), financing mechanisms , Global Environment Facility (GEF)) and multilateral partnerships )  support information sharing across the entire Swiss public administration and the coproduction of policy guidance , the document's section 6 ‘Perspectives on the future’ explores the challenge of further developing ‘a coherent Norwegian global health policy’ see ref.  p. 46 thThe rules for implementation in the Swiss policy are administrative because they provide the procedures for working across federal departments . The rules define how the co-ordination of the interdepartmental structures is part of a collaborative process for overseeing implementation of policy-related activities . A plurality of actors representing competing normative frameworks vie for policy attention and resources to support respective agendas for global health action in the global health governance system.52–54Both NPGH designs portray WHO, UN agencies, the World Bank, health-related multilateral organisations, and GHI and public–private partnerships  as key institutions for health and arenas for political mobilisation to support technical advancements in global health. Schneider and Ingram propose that groups targeted by public policy are depicted in normative terms because policy design contributes to the social construction of policy targets.Second, the implementation of NPGH may be elusive to health sector actors. Although both NPGH designs construct similar target populations, different instruments to reach them relate to who is responsible for implementation and according to what rules. Policy instruments are technical and social devices representing knowledge about how to coerce or enable a change in the target population.health and foreign affairs sectors are not homogenous groups of actors or expertise; diverse subgroups compose each sector . One caveat of conducting directed qualitative content analysis of policy documents is limitation for understanding the policy processes, negotiations between sectors and subsectors, and trade-offs in the content's production.These results and their implications for public health must be considered within the methodological and theoretical limitations of our analysis. The narrow concept of policy design we used confines the scope of policy content to texts of adopted NPGH strategy documents. This is an incomplete picture of content as theorised by Schneider and Ingram. Symbolic forms of content could be collected through interviews and other materials, but our analysis focused on single policy documents from two countries. Our deductive approach to using Schneider and Ingram's policy design elements also imposed limits. By applying generic categories of design elements to explore the content of NPGH documents, we might have omitted issues of focus in global health policy. For example, our analysis excludes discussion pertaining to the meaning of global health in NPGH and global health priority topics promoted by states for attention in the system of global health governance . Research has explained why certain policy issues receive political attention over others in the global health agenda,Global health policy and governance research generally focuses on how different frames of global health construct policy problems and legitimise the knowledge, actors and resources associated with their solutions.While there is no consensus on the understanding and use of the term global health governance in scholarship or practice,


Rana pipiens), is cytostatic and cytotoxic to variety tumor cell lines, inhibits growth of tumors in model animals and advanced to clinical trials as anticancer and antiviral drug [Onconase , a 12 kD ribonuclease from oocytes of northern leopard frogs (ral drug .et al., [In this issue of Oncotarget Vert et al.,  report oet al.,  explorinet al., .via decreasing resistance to apoptosis [The findings that ATF3 is the Onc target are in accordance with earlier reports that activation of ATF3 by other than Onc means triggers signaling pathways that lead to apoptosis in different types of cancers. Of particular interest are observations that overexpression of ATF3 increases cell sensitivity to variety of anticancer drugs. Thus, there is a remarkable correspondence between the mentioned above effects of ATF3 and Onc as factors increasing sensitivity of cancer cells to other treatments. Namely, dozens of papers describing ability of Onc to sensitize cancer cells to different anticancer drugs are recorded in PubMed. In some of these publications Onc is proposed to be used as an adjunctive therapy to amplify effectiveness of the primary treatment. The suppression of NF-kB by Onc was advanced to explain its ability to sensitize cancer cells poptosis . The invpoptosis .The noncoding RNA that provides regulation of genes activity via RNAi appears to be the potential primary target of this Onc. It was already demonstrated that Onc is able to attack siRNA within the cell and activate the siRNA-suppressed gene . It is pvia RNAi by Onc does not preclude the eventuality that other RNA species are targets of Onc as well. Both rRNA and tRNA have been shown degraded by Onc. Our early data on human submaxillary carcinoma A-253 and colon adenocarcinoma Colo 320 CM cells indicated that in addition to reduced clonogenicity the size of individual cells as well of cell clones was substantially smaller in the Onc treated cultures [Activation of ATF3 cultures  however


To evaluate the success of ultrasonography directed renal access in entering the target calyx from proper entry site and in the direction of renal pelvis during percutaneous nephrolithotomy (PCNL).PCNL cases who were operated on by one fellow from May-June 2014 were included in this study. A vertically placed ultrasound probe on the patient flank in prone position was used to identify the preselected target calyx. Needle was advanced through needle holder and fluoroscopy was used to document the entered calyx, site and angle of entry.Successful entering to the target calyx was achieved in 43 cases (91%). Successful entry with appropriate entry site and angle was observed in 34 cases (72%). Reasons for failure were minimal hydronephrosis, upper pole access and high lying kidneys.Although it is feasible to access a preselected calyx by ultrasonography guidance during PCNL, but entry to the calyx from the appropriate site and direction is another problem and needs more experience. In cases of minimal hydronephrosis, superior pole access or high lying kidneys, ultrasonography is less successful and should be used with care. Percutaneous nephrolithotomy (PCNL) is now the treatment of choice for surgical management of large renal stones. Fluoroscopy has traditionally been the method for obtaining access to the pelvicalyceal system. Later ultrasonography access to the pelvicalyceal system has been introduced and popularised by some researchers –8. It haA perfect percutaneous access tract to the pelvicalyceal system should be made through the tip of renal papilla in the targeted calyx and to be along the axis of renal calyx  so that The aim of this study was to access the effectiveness of ultrasonography guided PCNL renal access in entering the targeted calyx and in the direction of renal pelvis.Patients who were candidate for PCNL in Labbafinejad Hospital and were operated by one fellow during May-June 2014 were included. PCNL cases included patients with large renal stones (>2cm) or patients with renal stones >1.5cm in horseshoe kidneys. No specific exclusion criteria were applied and typical cases for PCNL within the study period were included. The operating fellow had prior experience in fluoroscopy guided PCNL (>400 cases) and in ultrasonography guided PCNL (>50 cases). PCNL was done according to the standard protocol described before . In brieIn this study proper entry site into renal calyx was defined as entry from the surface of renal papillae and not from the lateral walls of the calyx or any other entry sites. Proper entry direction was defined as the direction or angle that leads to renal pelvis . Tract wPlacement of nephrostomy or removal of ureteral catheter was done according to the judgement of the attending surgeons.The ethics of this study was approved by the local committee institutional board review. All patients were informed about the study and informed consent obtained.52 patients were enrolled during the study period. 5 patients were excluded from the study and their data is not presented in the below sections. Reasons for exclusion from the study were: fat body resulting in poor ultrasonic view of the kidney (1 patient), ectopic kidney with poor ultrasonic view (1 patient), high lying kidneys with poor longitudinal ultrasonic view because of rib shadows or stones in superior calices making ultrasonic view of the stone by ultrasonic probe in longitudinal view difficult (3 cases).Details of the 47 remaining patients and their operations have been outlined in A perfect access for PCNL should pass from the papillae into the collecting system and direction of the needle path should be coincident with the long axis of the target calyx . There hIn this study, we observed a high success rate for entering targeted calyx by ultrasonography guided renal access. Reasons for failure were: 1) minimal/no hydronephrosis in the target calyx. The absence of hydronephrosis makes identification of the stone and its surrounding calyx difficult on ultrasonography especially by less experienced urology surgeons. We usually inject normal saline through ureteral catheter in patients with nil-minimal hydronephrosis to augment the magnitude of hydronephrosis during the access phase of the operation. Another alternative can be injection of diuretic agents before the access phase so that the access time is roughly in the peak action duration of the diuretic agent 2). Failure to enter the preselected calyx was less often observed in lower calices in comparison with middle to upper calices. Therefore, in difficult or borderline cases, selection of lower calyx for entry especially in equivocal cases may be associated with a higher success rate. As illustrated in the methods section, appropriate entry site in this study was defined as the convex area of the tip of the calyx and not its lateral walls . ReasonsIn univariate analysis, right side PCNLs were associated with more frequent false entry sites . After pIn order to use ultrasonography for taking access in PCNL, there should be a clear view of the kidney calices on ultrasonography monitor. In situations in which this image is not clear, the success of ultrasonography in properly targeting the access calyx, its entry site or entry angle can be impaired. In our limited experience, this scenario happened in the following situations 1). A very fat patient with normal lying kidney with a 2cm stone in the lower calyx, 2) One muscular patient with body mass index of 27 with low lying mal-rotated kidney with a pelvis stone, 3) Three patients with stones in middle or upper kidney calices so that when the ultrasonography probe was placed longitudinally beneath the ribs, the view of the whole kidney or the segment containing the stone was not clear. In a few cases we tried to overcome this problem by angling the ultrasonography probe end caudally and pressing it on the patient back below the ribs but in these cases, this simple manoeuver could not solve the problem. Nevertheless, in such cases it is possible to obtain access to lower calyx without the need to observe the calices containing stones on ultrasonography monitor and then perform PCNL. In the protocol of the current study, we requested to have the image of kidney calices and containing stones which was not possible in the above cases but just for the sake of performing PCNL, it is enough to obtain ultrasonography guided access through a lower calyx and then perform PCNL by rigid or flexible nephroscope. Having mentioned these solutions, we think it is still safer to have fluoroscopy equipment at hand in such cases in case of failed ultrasonography guided access.We do acknowledge the operator dependency of ultrasonography a limitation of the results of this study. The experience of the operator can influence the obtained results. Nevertheless, there has been a publication by Japtag et al. in which the guidance of access by fluoroscopy versus ultrasonography yielded similar outcomes in hands of a trainee urologist with little prior experience in PCNL . It is nAlthough it is feasible to access a preselected calyx by ultrasonography guidance during PCNL, but entry to the calyx from the appropriate site and direction is another problem and needs more experience. In patients with minimal hydronephrosis, upper pole access or high lying kidneys this success rate is lower or the entry site into the calyx is less perfect. In such cases, it is advisable to have fluoroscopy equipment at hand.


General practitioner attitude questionnaires were sent in May 1987 to 525 general practitioners (GPs) within Avon. A year later a section dealing with the management of clinical situations was sent to 198 Avon consultants, to determine how they would ideally expect a GP to respond to these situations.The majority of both the GPs and consultants held a common viewpoint, but significant differences were noted between the consultants and GPs in six out of the ten situations. Consultants with more than six months' GP experience had fewer significantly different views than their colleagues with little or no GP experience. GPs and specialists under the age of 45 years also had fewer significant differences in management than older GPs and specialists. The differences seem to reflect the clinical focus and interests of each professional group. We believe vocational training is a contributory factor to the differences and support the General Medical Council's proposal of a broader post registration training for all doctors.


The complex nature of studying health and healthcare disparities in general, and in the context of the Israeli healthcare system in particular, is depicted in two recent IJHPR articles. The first examines Emergency Department (ED) waiting times in a tertiary children’s hospital and the second examines disparities in the health care for people with schizophrenia of an ethnic-national minority. Contrary to other Israeli studies on wide disparities in health and healthcare, these studies show no disparities -  ED waiting times did not differ among Arab and Jewish children and report no differences in performance of Hemoglobin A1C tests or in surgical interventions in patients with cardiovascular disease between Arabs and Jews with schizophrenia. Thus, the studies reflect areas of equitable health care delivery within the Israeli healthcare system.Future studies should account for the fact that the phenomena of health and healthcare disparities is complex and should utilize rigorous methodologies to take into consideration the various factors that may affect the manifestation of differences amongst population groups. As a result, they may help detect disparities which may otherwise be missed. Two recent Israel Journal of Health Policy Research articles depict the complex nature of studying health and healthcare disparities in general and in the context of the Israeli healthcare system in particular. Feldman and colleagues  studied The two papers present an impressive platform for the study of ethnic disparities within vulnerable population groups, namely children  and patiThese findings should be evaluated in light of the multifaceted makeup of the Israeli society and its healthcare system, within a comprehensive approach that accounts for the various types of interrelated social determinants of health  and the Despite universal coverage and a national health insurance law in Israel since 1995, a wide-array of gaps in health care service use have been extensively documented, including, as also exemplified by Gal and colleagues , lower rThe null findings regarding disparities in most of the indicators reported by Gal and colleagues  may reflHowever, it is not possible to rule out that the lack of disparities reported by Gal  and collThe lack of disparities reported by Feldman and colleagues  presentsAdditionally, Feldman and colleagues address a potential reason for disparities in waiting times by differentially examining waiting times by ethnic concordance. Contrary to other studies, concordance between providers and patients was not related to differentiated waiting times. For example, in a study on patient-provider language concordance and the quality of transitional care in oncology patients at the same hospital , Rayan et al. report that language concordance was associated with higher ratings of the care transition experience by Arab and immigrant minority groups compared with the general Hebrew speaking population .To conclude, the findings on the mainly lack of differences amongst Arabs and Jews in treatment of chronic comorbidities in schizophrenia patients  and in pThe phenomena of health and healthcare disparities is complex and should utilize rigorous methodologies to account for the various factors that may affect the manifestation of differences amongst population groups. Rigorous methodology may help detect disparities which may otherwise be missed.


The majority of these designs have reused naturally occurring protein structures as ‘scaffolds’ onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increased search space, but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process.The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the  No new data was created during the course of this research.The Authors declare that there are no competing interests associated with the manuscript.


We thank Morfeld and Erren for their continued interest in the WHO Health risks of air pollution in Europe (HRAPIE) report (WHO Regional Office for Europe The HRAPIE report itself clearly spells out the limitations of calculating ‘premature deaths’, on pages 15 and 16 (WHO Regional Office for Europe Appreciating the limitations of death counts as a metric for quantifying disease burden due to exposure to air pollution and other risk factors, the widely cited global burden of disease exercises have since their inception quantified such burdens both in terms of the number of deaths in a given year attributable to past exposure and in terms of lost years of healthy life, or DALYs (Murray and Lopez We appreciate the opportunity for clarification of the HRAPIE report, article, and first response and agree with Morfeld and Erren that estimated burdens of disease attributed to air pollution need to be correctly interpreted in the context as explained in more detail above and in the quoted references.


Imprinted genes are a subset of genes that are expressed from only one of the parental alleles. The majority of imprinted genes have roles in growth regulation and are, therefore, potential oncogenes or tumour suppressors. Cancer is a disease of aberrant cell growth and is characterised by genetic mutations and epigenetic changes such as DNA methylation. The mechanisms whereby imprinting is maintained in somatic cells and then erased and reset in the germline parallels epigenetic changes that cancer cells undergo. This review summarises what we know about imprinting in stem cells and how loss of imprinting may contribute to neoplasia.


The use of non-invasive brain stimulation (NBS) such as transcranial magnetic stimulation (TMS) and direct current stimulation (tDCS) has significantly advanced our understanding of the mechanisms underpinning motor and cognitive processes in the brain. Repetitive TMS (rTMS) and tDCS have the potential to induce bidirectional changes in cortical excitability and lasting neuroplastic effects that are dependent on the nature and parameters of the stimulation used  . For insIn particular, the application of interventional forms of NBS in neurological disorders such as Parkinson’s disease (PD) has been viewed with great interest. PD is a chronic neurodegenerative condition that stems from a loss of dopamine-producing neurons in the substantia nigra within the basal ganglia (BG) . While tApart from changes in intracortical excitatory and inhibitory neural circuitry, PD is associated with pathological neural oscillations that are thought to underpin motor dysfunction . While mInterventional forms of NBS can have a positive effect on motor and cognitive function that is likely to be driven by a change in cortical excitability of specific brain areas . To dateOf interest, variant forms of NBS, which are frequency specific such as transcranial alternating current stimulation (tACS), are gaining increasing interest for their ability to induce lasting neuroplastic and functional change . tACS isWhile there is some evidence to support the concept that neural entrainment using tACS improves motor function in healthy individuals , 36, theTo this end, we acknowledge that the scarcity of information surrounding the effects of tACS on neural entrainment limits our interpretation of early studies in healthy individuals and people with PD. Research into the therapeutic potential of tACS is still in its early days, and there is much that is not known about the causal relationship between dysfunctions in neural oscillations and specific motor and cognitive deficits in PD. While studies by Brittain et al.  and KrauAll the authors  contributed equally to the manuscript.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.


Staphylococcus aureus infection  as well as replication studies in well-characterized patient cohorts may improve our understanding of the potential role of inflammation in disease pathogenesis and open up new avenues of therapeutic intervention.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In April 2013, a case of wild polio virus (WPV) was detected in the Somalia capital Mogadishu. This inaugurated what is now referred to as the 2013-2014 Horn of Africa Polio outbreak with cases reported in Somalia, Kenya and Ethiopia. By the notification of the last polio case in August 2014, 223 cases of WPV had been reported in Somalia, Kenya and Ethiopia of which 199 in Somalia alone. The outbreak response required timely exchange of information between the outbreak response coordination unit (in Nairobi) and local staff located in multiple locations inside the country. The need to track and timely respond to information requests, to satisfy the information/data needs of polio partners and to track key outbreak response performance indicators dictated the need to urgently set up an online dashboard. The Somalia Polio Room dashboard provided a graphical display of the polio outbreak data to track progress and inform decision making. The system was designed using free and open sources components and seamlessly integrated existing polio surveillance data for real time monitoring of key outbreak response performance indicators. In this article, we describe the design and operation of an electronic dashboard for disease surveillance in an outbreak situation and used the lessons learned to propose key design considerations and functional requirements for online electronic dashboards for disease outbreak response. Polio is a disease targeted for elimination since 1988 when the World Health Assembly voted to eradicated polio . In ApriIn a management and information system standpoint, a dashboard is “an easy to read, often single page, real-time user interface, showing a graphical presentation of the current status (snapshot) and historical trends” . StephenPolio outbreak response is data and information intensive. Timely and accurate information from field activities are required 1) to monitor key performance indicators to measure progress towards planned goals and timely identified deviations from planned goals and implement corrective measures; and 2) to assess the impact of outbreak response activities. Dashboards are not new in public health; however, their use in disease outbreak response at country level by national programs is not very well documented. Notable examples of the use of dashboards include multiscreen displays of disease and outbreak information at the Centers for Disease Control Emergency Operation Centers  or at thData inputs: the system was designed to use acute flaccid paralysis (AFP) data as the primary data source. AFP describes a sudden onset of weakness or paralysis, affecting mostly motor muscles of lower limbs in children. AFP is the main clinical presentation of poliomyelitis disease [ disease . PatientThe AFP database served as the primary source of data for the dashboard to avoid interfering with ongoing AFP surveillance and data entry processes; no new data source was created or required. A tab-separated text file containing selected AFP data elements  was generated from the AFP main database and imported into the system. On upload, the text file was processed and the key data elements stored in a table in the MySQL database. To accommodate for early notification of cases, a user protected area allowed for the manual entry of AFP cases by surveillance officers located in districts through a customized online form. Additional data streams used by the system are shown on Geo-mapping: the systems integrates Google Map API to display the location of AFP cases. Since geolocation information of AFP cases are not available, we used the latitude and longitude coordinates of the capital city of district of residence of the AFP case as a proxy to the geolocation of the AFP case. The altitude and longitude data of all district city capitals were extracted from the geo-name server table [er table  for SomaGraphical display: the visual interface of the system was specifically designed for display on high resolution/large monitors in the outbreak control room located in the WHO Somalia Liaison Office in Nairobi. Six rich individual displays existed and combined maps, graphs and tables summarizing the current status of outbreak response and AFP surveillance activities. During its 15 months of existence (July 2013 to Oct 2014), the Somalia Polio Room Dashboard, by integrating various outbreak and surveillance response data sources into rich graphical interfaces provided an easy-to-read information to polio outbreak response managers, responders and immunization partners located in various areas inside and outside of the organization. A polio outbreak response involves a multitude of players at various levels of the same organization or outside of the organization. The ongoing analysis and sharing of information with all these players can place an undue burden on surveillance staff and data managers. With the Somalia Polio Room Dashboard, we were able to reduce the need of daily analysis and sharing of outbreak information, thereby release surveillance staff from the need to response to multiple information requests from various sources.The methodological innovation of the system can be viewed at various levels: 1) we demonstrated the possibility of designing, at country level, an effective data visualisation tool using available and free technology in a limited amount of time; 2) we demonstrated that the use of a visualisation tool accessible to all partners can significantly reduce the time spent on routine analysis and other reports.Lessons learned on key considerations for dashboards for outbreak response In his 2006 essay on dashboard design, Stephen Few provided 13 pitfalls for dashboard design [d design . These pThe need for a dashboard is established: are existing data visualization, analysis and sharing mechanisms and tools sufficient or is there a clear need for additional or expanded data visualization tools? Knowing who has interest in accessing the dashboard should be the main determinant of whether or not to pursue the project of developing a dashboardcritical advantages over existing data exchange mechanisms and formatsThe dashboard should provide The need of the dashboard should be established for a reasonable period of time: establishing that the need for a dashboard will be sustained for an acceptable period of time should help decide whether investing time and efforts into the development of a dashboard is warrantedStructured and regularly updated data streams exist: to feed the need to constantly update the rich visual display of the dashboard; a dashboard that is not updated regularly loses its appeal. The dashboard should use existing data and should not require new data collection processesThe workload and skills required to update and operate the dashboard should be nil to minimal on the outbreak response staff: during an outbreak, the surveillance staff including data managers and data entry clerks are overburdened and should not be distracted by new processes or long trainings on how to operate the dashboardThe dashboard should be designed for scalability and flexibility: and should easily accommodate the changing information requirements of the outbreak response; it should be easy to add, remove or modify the visual display or other processesopen sources or free technology and web-services to minimize the cost of the dashboard developmentUse of available, preferably We have demonstrated that it is possible to develop an online electronic dashboard for outbreak response using existing open source and free tools. The development of such dashboard requires technical expertise but should also be carefully examined in the light of the considerations we identified. The Somalia Polio Room Dashboard clearly demonstrates the usefulness of electronic dashboard in outbreak response through their ability to improve information sharing and minimize the time spent on multiple information requests; their use should therefore be encouraged. The technical expertise in computer programming, data management and software design required to set-up functional and useful electronic dashboards remains a limitation. To address these limitations, technical partners including WHO should develop and avail ready-to-use/easy-to-setup dashboards for outbreak response.The authors declare no competing interests.


In this study we used a model of adult learning to explore undergraduate students’ views on how to improve the teaching of research methods and biostatistics.This was a secondary analysis of survey data of 600 undergraduate students from three medical schools in Uganda. The analysis looked at student's responses to an open ended section of a questionnaire on their views on undergraduate teaching of research methods and biostatistics. Qualitative phenomenological data analysis was done with a bias towards principles of adult learning.Students appreciated the importance of learning research methods and biostatistics as a way of understanding research problems; appropriately interpreting statistical concepts during their training and post-qualification practice; and translating the knowledge acquired. Stressful teaching environment and inadequate educational resource materials were identified as impediments to effective learning. Suggestions for improved learning included: early and continuous exposure to the course; more active and practical approach to teaching; and a need for mentorship.The current methods of teaching research methods and biostatistics leave most of the students in the dissonance phase of learning resulting in none or poor student engagement that results in a failure to comprehend and/or appreciate the principles governing the use of different research methods. Research is globally recognised as a major output of universities and other institutions of higher education. On the other hand the teaching of research methods has received a limited amount of attention , 2. AlsoPlease suggest any ways in which your undergraduate teaching in research methods and statistics could have been more useful?”. It is important to note that the pharmacy and nursing programs have a research project as a requirement for the award of the degree at all the three universities. The students’ responses were previously captured verbatim in Epidata and then exported to Microsoft word for editing before being saved as a single text file for analysis. The responses were then subjected to qualitative phenomenological data analysis informed by the model of adult learning proposed by Taylor and Hamdy (2013) [This was a secondary analysis of undergraduate student's survey data from three purposively selected public medical schools in Uganda namely: Makerere University College of Health Sciences (MakCHS), Gulu University (GU) and Mbarara University of Science and Technology (MUST) . All they (2013) , using ay (2013) , 19. The“Sometimes we carry out research and fail to analyse or understand it because of very little or no information on biostatistics”2nd year Female Medical Radiology student.There were 600 respondents to this survey of whom 516 responded to the open-ended question. “Undergraduate teaching in research methods provides a unique opportunity to follow your interest in an area of research to focus on this for several years and make an impact” 3rd year Male Medical Radiology student. The items coded under relevance pointed to the students desire to understand why they were learning the research methods now. In summary the students thought the teaching of research methods would make the teaching of other subjects more relevant, promote the use of a common scientific language, impact the communities from which the students came from and make journal reading easier. Also under relevance the students wanted to see the societies they got the information from benefiting from the research findings as captured in this quotation: “It could be more useful if the statistics obtained were used to improve health in the regions from which the statistics were obtained” 2nd year Male Medical Radiology student. The next code was on teaching with 44 codings. In this code student concerns on who was teaching the course were identified. The concerns ranged from the level of expertise of the teacher to how the teachers presented their material. Some of the students desired to learn the material under less stressful learning conditions for example in the morning as opposed to before lunch as seen in this quotation. “If only they (lectures) can be before lunchtime with more vibrant lecturers and a bit practical it would help” 4th year medical student The next frequently cited code in this item was the courses with 41 codings. The students thought that the course material should be delivered as a stand-alone mandatory course with clear course content and examination leading to credits that appear on their transcript. Some of the student even suggested that a department should be created in the university to handle the teaching of research methods and biostatistics. The last code under dissonance was content with 28 codings. In this code student's suggestion for additional content in the form of exams, books available, software and scheduling were captured. The students also suggested that the exposure to this content should be repeated with increasing detail for deeper learning as they matured in their academic programs (see “If we had data collection practically immediately after studying the theory and not wait for years” 1st year female medical student.The next most frequently identified code in this theme was time with 76 codings see . In thisrams see . The nexrams see . The opp“Lecturers who understand that field” 3rd year male medical student The last theme was that corresponding to the consolidation phase of the adult learning model [“Biostatistics learning should be gradual right from year 1 semester 1 and should be applied more prominently in COBES” 2nd year female pharmacy student.The next code group in this theme was mentorship with 24 codings. In mentorship students identified the need for opportunities for guided practical learning through involvement in departmental research, or engagement in the activities of different research organizations as a form of mentorship. Learning to do research in an area of interest to the mentor would result in greater mentor engagement in the learning process. This engagement is driven by the quality of feedback the mentor provides. The students linked the quality of feedback to the level of interest the mentor had in the area of research. ng model . In thisThis study set out to explore students’ views on how to improve the teaching of research methods and biostatistics at three Ugandan public universities. The students who participated in the study appreciated the importance of learning research methods and biostatistics as a way of understanding research problems and appropriately interpreting statistical concepts during their training and post-qualification practice. They also identified the limited time allotted to teaching and inadequate educational resource materials as the main impediments to effective learning of research methods and biostatistics. They proposed several suggestions on ways to improve the teaching and learning of research methods and, ways of effectively utilizing the little time allotted to this course with a strong emphasis on putting what is learned into immediate practice as expected according to the principles of adult learning . Health “Biostatistics learning should be gradual right from year 1 semester 1 and should be applied more prominently in COBES”. Some of the shortcomings of this study included the use of inherently biased qualitative approach for the analysis of short open-ended responses to the probe question. Whereas the results of the analysis are very context specific, the number of respondents created an opportunity to do tallies that can be used as a rough indicator of where the institutions represented in the study lie with respect to the used adult learning model. Future studies may need to use more in-depth approaches involving more stakeholders. Despite the shortcomings the study findings are relevant at both the institutional and individual levels. For the student, it is important to foster student interest in research methods. The ease of understanding statistical and research concepts is directly dependent on the student's interest in the subject [Another example of the students identifying adult approaches to learning is seen in suggestions to increase learning and developing durable skills in critical appraisal and statistical interpretation. Students proposed early and continuous exposure to research methods throughout the course of their academic programs. This they suggested should be complemented with; additional web based educational resource materials; and more hands-on practical teaching approaches such as case study interpretation, participation in research and publication writing. As students mature they become more independent and self-directed. Thus, they have to practice as this is the most effective way of teaching and mastering statistical skills . Some au subject . Since m subject .This study has highlighted several challenges faced by students in public universities in learning research methods and biostatistics. In view of the large number of suggestions clustered under the dissonance phase of learning we conclude that the current teaching of research methods is not adequately engaging students in the learning process. This has resulted in the students’ failure to comprehend and appreciate the underlying principles governing the use of the various research methods. There is thus a need for the participating institutions to make individual learner and institutional adjustments to align the teaching of research methods with their vision and mission statements.Health professional training curricula have increasingly become congested leading to the allocation of inadequate time to hands-on teaching of research methods and related research statistical approaches;Much of the university teaching on research methods focuses more on knowledge transfer, while giving little or no attention to context and application of the acquired knowledge;Students’ research outputs count greatly to research related status of most institutions of higher education, thus keeping track of student’ research related expectations and performance is a key quality control measure.The current methods of teaching research methods leave most of the students in the dissonance phase of learning resulting in none or poor student engagement that results in a failure to comprehend and/or appreciate the principles governing the use of different research methods;Research methods and biostatistics should be delivered as a stand-alone mandatory course with clear course content and examination leading to credits that appear on academic transcript;Individual learners and academic institutions should make adjustments to align the teaching of research methods with their vision and mission statements.


Primary emotional systems and personality Christian Montag and Jaak Panksepp analyze how emotional systems are involved into the development of basic personality into an evolutionary framework. They also stress the importance of such investigation for the promotion of human welfare in the context of psychiatric research and practice . Sentiments and character do not exactly overlap with emotions and personality because they are the product of social interactions, civilization processes, and reflective activities . Highlighting the mechanism underlying personality development and its link to emotions can offer a solid ground for empirically tenable views on moral education. The interest of this last topic is not purely theoretical, but progress in this field could foster human welfare (as recommended by Montag and Panksepp themselves). Here it is not possible to argument, but it is very likely that an empirically informed sentimentalist view would strongly discourage rigoristic views of moral education and would confirm Hume's ideas about the so called “monkish virtues” Davie, . A scienThe author confirms being the sole contributor of this work and approved it for publication.The author declares 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 objective of this study was to compare performance on different versions of the running span task, and to examine the relationship between task performance and tests of episodic memory and executive function. We found that the average capacity of the running span was approximately 4 digits, and at long sequence lengths, performance was no longer affected by varying the running span window. Both episodic and executive function measures correlated with short and long running spans, suggesting that a simple dissociation between immediate memory and executive processes in short and long running digit span tasks may not be warranted.


Physical activity promotion has met with limited success across a range of demographic indicators, largely due to our poor understanding of how drivers of physical activity behaviours vary by context and setting . DespiteNine articles focused on physical activity among children and adolescents. Best and colleagues addressed the methodological issue of measurement heterogeneity by exploring predictors of children’s physical activity that emerge regardless of whether objective or self-reported physical activity data are considered. Enjoyment, parent support and availability of sport facilities emerged as consistent predictors, suggesting that these factors should be prioritized as intervention and policy targets. The challenges of integrating physical activity options into school curriculum were addressed in a qualitative study reported by van den Berg and colleagues who interviewed primary school teachers and principals in The Netherlands. The battle for curriculum time, also reported elsewhere  was evidThe majority of studies of adult physical activity focused on aspects of the built environment, with two studies examining this from a socioeconomic perspective. Zandiah and colleagues used Geographic Positioning System technology to compare high and low SES neighborhoods in The Netherlands on components of walkability for older adults. Disparities in walking across SES gradients could be related to availability of green spaces and recreation centres. Highlighting the need to consider influences of physical activity in context, Micklesfield and colleagues reported that the influence of SES on physical activity among young South African women depended on whether they lived in urban or rural areas. In accord with this observation, Berry and colleagues found that neighbourhood walkability was directly associated with walking behaviour in urban but not rural Australian adults. The authors suggested that context-specific measures of walkability need to be developed to better understand the environmental influences that seem to be unique to rural settings. The challenges of promoting physical activity in rural areas of the USA were investigated by Lo et al., with residents’ preferences for structured and socially supportive settings discussed against a backdrop of limited resources to effect rapid change in these communities. The authors suggested that small, staged improvements to existing features were key to meeting substantial longer term targets. Costigan and colleagues identified features of public parks that should be targeted for improvement in their study of park use for recreational physical activity among Australian adults. Ease of access, provision of shade, safety and regular maintenance were strongly supported. Interestingly, the availability of recreational dancing in public parks was associated with overall physical activity among Colombian women, as reported by Sarmiento et al. All but one of the studies of built environment influences on physical activity were cross-sectional in design and therefore unable to identify the impact of changing salient environmental features on consequent physical activity behaviours. McCormack and colleagues’ elegantly designed study tracked Canadians who changed residence in the previous 12 months, and confirmed a relationship between changed neighbourhood walkability and changes in active commuting. The only study of social influences on adult physical activity came from Westgarth and colleagues who provided intriguing evidence for a ‘mutualistic’ association among dog owners and their dogs during walking. Dog walkers were strongly motivated by the sense that the dog also enjoyed the experience, much more so than other potential influences such as exercise benefits and social interactions while walking.This collection of studies confirms that physical activity behaviours are shaped by all levels of the social ecological framework as well as interactions among these levels, resulting in a complex causal web of factors. To advance our understanding to the point that interventions targeting social and physical environmental influences on physical activity can be designed with confidence, research efforts need to continue to focus on context- and setting-specific factors that are amenable to change within demographic groups differentiated by age, gender, social disadvantage and geographic location.


Robotic radical prostatectomy (RRP) has become an effective modality in the treatment of localized prostate cancer. We detail the experience at our institution and provide a perspective for future considerations of RRP with respect to improved preoperative imaging and surgical instrumentation.


Paliperidone palmitate is a 2nd generation long-acting injectable (LAI) antipsychotic which is increasingly prescribed for patients with chronic schizophrenia. However, it is more expensive than 1st generation LAI antipsychotics and little is known about its effectiveness in a real world clinical setting. We sought to address this issue by analyzing a large electronic case register of patients with schizophrenia treated with LAI antipsychotics.Data were obtained from 1,281 patients in the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register who were treated with an LAI antipsychotic between 1st April 2011 and 31st January 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were extracted using the Clinical Record Interactive Search tool (CRIS) and analyzed in each of the 3 years before and after LAI prescription using multivariable regression.Patients who received paliperidone palmitate  spent more time in hospital  and were admitted to hospital more frequently  in the year prior to treatment than those treated with other LAI antipsychotics . However, there were no significant differences between paliperidone and the other LAI antipsychotics in the 3 years after initiation with respect to the number of days spent in hospital  or frequency of hospital admissions .Paliperidone palmitate was more likely to be prescribed in patients with more severe illness, as indicated by a history of more frequent and lengthy hospital admissions prior to initiation. The absence of differences in outcomes after initiation indicates that the effectiveness of paliperidone palmitate was similar to that of other LAI antipsychotics. However, paliperidone palmitate may be better tolerated than other 1st generation LAI antipsychotics with a lower rate of discontinuation. These findings merit consideration in relation to the high cost of paliperidone palmitate compared to other LAI antipsychotics.