In Pakistan, Contraceptive Prevalence Rate (CPR) among married female youth is 17.4% and even lower in rural and slum areas leading to rapid population growth on one hand and poor health consequences on the other. The study was conducted to explore family planning service providers’ perceptions regarding use of different contraceptive methods and to identify factors that are influencing their use amongst currently married youth aged 18-24 years in slum areas of Karachi.Qualitative exploratory study design was adopted and a total of ten in-depth interviews were conducted with family planning service providers of the area. For content analysis coding of transcribed interviews was done and then categories were made and furthermore themes were derived.Our findings revealed that family planning service providers perceived that there is low use of contraceptive methods amongst youth of study area and low usage could be due to side effects; myths and misconceptions; lack of proper knowledge about different contraceptives; unmet needs of contraceptives; socio-cultural and religious factors about different contraceptive methods and family planning service providers own biases against or for use of contraceptive methods amongst youth in the study area. However better education of youth and family planning service providers’ improved knowledge about counseling and use of contraceptive methods was perceived to be associated with improved use of family planning methods amongst youth of the study area.Exaggerated side effects and socio-cultural factors could be important influences leading to low use of family planning methods amongst youth of Karachi. Some policy initiatives are the training of lady health Workers, lady health visitors, physicians and staff of the pharmacies for counseling youth in the correct use of family planning methods. Being one of the poorest and sixth populous countries of the world , PakistaTo date voluminous studies have explored the determinants towards the use of different contraceptives methods among married couples across the globe . FurtherThe study was conducted in Korangi town (UC 2 and 3), Karachi, Pakistan from July to September, 2010. Exploratory qualitative study design was adopted using in-depth interviews with family planning service providers. In order to capture as many aspects and views of family planning service providers, the participants were chosen purposively .The study participants included: Family Planning Service Providers from the 2 Union Councils of Korangi town. They included 2 physicians, 4 Lady Health Visitors, 2 Lady Health Workers and 2 medical store drug providers. Lady Health Workers working in the area facilitated the identification of family planning service providers. Inclusion criteria being family planning service providers of UC 2 and UC 3 of Korangi town, Karachi, Pakistan and those who gave consent for IDIs.A topic guide was used to guide the discussions . The entContent analysis was the strategy used for analyzing the transcribed interviews. We considered a meaning unit as words, sentences or paragraphs containing aspects related to each other through their content and context . TherefoStudy was approved by Ethical Review Committee (ERC) of Aga Khan University (AKU) Karachi, Pakistan. The hard copies of the interviews and all audiotapes were kept in lock and key. Verbal and written consent was sought from all study participants.Transcription was done on the day of the interview to ensure that there is minimum time lapse so that the data on tapes is transcribed to the paper with the fresh memory. All of the authors were competent in the local language and the cultural meaning of the content . Recordings and notes were also consulted for any verification at the end of the interview with the interviewees. Interviews were transcribed into Urdu and then translated to English by the Principal Investigator. Credibility was maintained by selection of context, informants and well-structured in- depth Interviews. Conformability was achieved through separate coding by the first and third author, whereby similarities and dissimilarities were discussed. Consensus on codes and categories was thereafter reached. During the analytical process, the first and third author thoroughly discussed the structure of codes, categories and themes. All authors read, discussed and agreed on the final categorization and themes. Two of the authors (NN and SA) agreed in the way the codes and categories were labeled and categorized, which in later stages were verified by the other two authors (FH & NS). Transferability was achieved through purposive selection of informants with different background characteristics such as profession  educational level and experiences. Dependability was enhanced by conducting the IDIs over 2 months, to ensure that the phenomena under study did not change. All IDIs were conducted in Urdu, moderated by local researchers well versed with the context, transcribed into English by the principal investigator and analyzed within a week. Verification of transcriptions was done by the first author who listened to the audio-tapes twice. The quotations given in the study are intended to facilitate the reader’s evaluation of the creditability of results (JQM 2006).Results were obtained by content analysis keeping in mind objectives of the study. Two underlying themes emerged during the analysis: barriers of family planning methods use and facilitators of family planning methods use . For thiOn Content analysis, there appeared to be multiple determinants of use of contraceptive methods as shown in Exaggerated side effects of different contraceptive methods were considered as one of the main reasons for discontinuation of Family Planning methods.Family Planning service providers shared that Intra Uterine Contraceptive Device (IUCDs) has most of the side effects.“Many women complain that IUCDs make their husbands uncomfortable during intercourse because of the thread that protrudes. Therefore, IUCDs are not well liked by the general population.” (….interview 9)“Most women taking OCPs complain of dizziness & nausea. Even if she convinces them to take the pills they, automatically, get turned off because of the side effects.” (….interview 3)Likewise most of the family planning service providers were of the view that youth of the area think that vasectomy is causing physical weakness in males and tubal ligation is the causing weight gain in females as a side effect.Family Planning service providers of the area shared that myths and misconceptions about different contraceptive methods are also potential factors for not using contraceptive methods amongst youth in the study area.“In general, men do not realize or care for the problems that their wives are going through. They do not agree to undergo vasectomy as they are afraid it will make them impotent” …. (interview 2)“Many of the women shun IUCDs because they believe that IUCDs can cause infections, destroy the uterus somehow & that is can travel up from the uterus into the abdomen.” …. (interview 7)“Usually they don’t have misconceptions about injections. If they have a big family, they frequently use injections” …. (interview 4)“After using family planning method, the ovary of females will become dry and then they will not be able to have children …. (interview 10)Majority of family planning service providers shared that youth of the area perceive that condoms cause inflammation, infections and ulceration in both males and females. Most of the Family Planning service providers said that none of the males in the area want to opt for vasectomy as they believe that vasectomy causes physical weakness and impotency.This also emerged as one of the probable determinants for non-use of Family Planning methods amongst youth of the area as some of the Family Planning service providers shared what youth of the area perceived“Pills are difficult to remember & these women become very upset often missing a dose & do not understand what to do next.” … (interview 6)All the FP service providers were of the view that education is one of the most important factors in improving CPR. Moreover some of the FP service providers shared that certain ethnicities as Bengali and Sindhi believe that big family size is associated with more respect in the society.Most of the family planning service providers shared that Pakistan is a patriarchal society as shared in the quote by an interviewee.“Role of mother in law and husbands is pivotal in decision making for the use of contraceptives.” … (Interviewee 8)Family planning providers also shared that some people of the area believe that if someone prevents pregnancy, Allah makes them ill in some other way for example blood pressure and diabetes and there is a common belief that Family Planning is forbidden in our religion.One of a Family Planning service provider shared that“Youth of the area thinks that their prayers will not be accepted if they use Family Planning methods” … (Interviewee 5)Some of the family planning service providers have their own biases towards the use of contraceptive methods as stated by one of the interviewee.“I don’t recommend contraceptive methods like IUCD, injections and pills to youth females and maximum I council them for using condoms or natural family planning methods” … (Interviewee 1)Better knowledge of Family planning service providers and improved education of youth are facilitating the use of family planning methods as discussed below.Some of the family planning service providers themselves identified that knowledge of the family planning service providers about counseling youth for use of contraceptive methods is very important in this aspect and facilitate the use of these methods amongst youth of the area.“Injectables are not liked by women of the area; tend to cause excessive bleeding, due to hormonal imbalance. Therefore, does not prefer injectables to anemic women.”… (Interviewee 8)“Misconception is rampant among the females who come to her is that IUCD moves up to the stomach. I, myself believe that mostly what actually happens is that the IUCD is expelled during menstruation and these women do not realize it.”… (Interviewee 1)All the interviewees unanimously agreed that mostly, if the client seeking family planning services is better educated at-least (uptill grade 10), they will understand the importance of family planning methods use and will be much more compliant to the use of contraceptive methods.This paper has tried to add to existing evidence on factors that support or constrain the use of family planning methods and two broad themes were identified as barriers to and supporters of the use of family planning methods amongst youth of study area. We have identified many demand side barriers to the use of family planning methods use as mentioned in the study where the author has shared that demand side barriers to health services access are abundant in low- and middle-income countries and there is a lack of evidence on ways to reduce them . In our In family planning service providers’ perceptions, illiteracy was also identified as one of the constraining factor, whereas better education of youth were identified as a supporting factor towards the use of family planning methods use. It is thought that better educational completion operates through multiple factors to influence family planning service use, encompassing female decision-making power and increasing awareness of health services . Women with no education were most likely to report psychosocial barriers to the use of family planning services. A woman’s involvement in education may also increase her exposure to the health system and improved use of services . ExploraThis study addresses the reproductive health issues of youth in a community setting and in depth interviews responses explicated from Family Planning service providers were valuable and based on their observations & experiences, which is one of the strength of this study. Moreover findings documented by this study would assist in planning and undertaking policy initiatives to streamline recommendations for improving the use of different contraceptive methods amongst youth in slums of Karachi. It was a not a large population study due to paucity of funds and time due to which it has certain shortcomings, the important of which are: few interviews with the respondents were not conducted in depth due to increase patient load at their offices; extreme hot weather in the month of data collection and some of respondents unwillingness to give more time for interview. One weakness of the study might be that the data were initially collected in Urdu, translated to English and analyzed in the English version. However, a multidisciplinary team with experienced qualitative researchers took part at all stages of the research process.In the light of findings of the study and suggestions by the interviewees during in-depth interviews, some of the recommendations to address the low use of contraceptives are that there is a need to disseminate correct information on the use of contraceptive methods. It will help in removing related misperceptions about Family Planning methods through easy to understand booklets in local languages. The initiative should also include other opinion leaders in the society such as prayer leaders, school teachers, local political and social workers. It would help change the societal mindset regarding many aspects such as baseless myths. It will also help to rectify religious and cultural misperceptions. Some urgently needed policy initiatives to improve the use of contraceptives are: lady Health Workers, lady Health Visitors, physicians and staff of the pharmacies are needed to be trained for proper counseling for correct use of family planning method. In conclusion, contraceptives use amongst youth is low in the study area; in addition lack of appropriate knowledge about contraceptives contribute for low CPR among the youth and side effects; some religious and socio-cultural beliefs about different contraceptive methods could be potential determinants contributing to low use of contraceptives.


Gliomas, the most frequent tumours occurring in the CNS, are defined and graded on the basis of histological features to predict prognosis and management. Owing to biological heterogeneity, the histological diagnosis and expected clinical outcome do not match in a significant number of patients. The combination of imaging and gene expression, referred to as “radiogenomics,” has the potential to give insight into tumour biology that would be difficult to acquire from either technique alone.• Throwing light upon individual imaging feature and biological/ molecular alterations, analyses that may detect subsets of morphologically identical tumours with different clinical behavior (diagnostic markers).• Classification and grading of Gliomas as per Haarlem consensus.• Imaging features of glioblastomas may correlate with molecular mutations.• Identification of imaging parameters that has the potential as a non-invasive biomarker for common molecular mutations associated with gliomas and their associated clinical impact.• Review of current radiogenomics literature.• Given the noninvasive nature of medical imaging and its wide use in clinical practice this approach facilitates the association of complex molecular signatures with readily identifiable imaging characteristics.• As we move toward a more individualised approach to therapy for glioblastoma on the basis of its specific genetic and biochemical features, radiologists may contribute to the future development of targeted agents for treatment of glioblastoma.


Good information on the harm of a drug is vital to inform risk-benefit decisions and undertake robust cost effectiveness analysis. Clinical trials reported in peer-reviewed articles are not useful for this purpose ,2. RegulInclusion: Antidepressants/antiepileptic brand drugs evaluated in randomised trials of neuropathic pain and marketed in the US and Europe. Documentation was obtained from the European Medicines Agency and Food Drug Agency.Twelve brand drugs with matching SmPC and USPI were included. The number of harms ranged from 56 to 265 for SmPC and 65 to 425 for USPI Table . On averIt is expected that the harm profile in the product information for the same drug should agree. This study found a lack of consistency for the same drug based on the same central data available to the pharmaceutical company, and demonstrates the overwhelming impact of using arbitrary rules for reporting and differing dictionaries to code harm data. This problem can only be exacerbated across drugs.The development of CORE harm outcome sets by drug class would improve the usability of this information by facilitating comparison of harm profiles across drug which would support informed risk-benefit decisions and allow robust cost effectiveness analyses.


Every day seems to bring a new development in the treatment of chronic total occlusions (CTOs). The interest in this field is to be welcomed, given the rapidly increasing procedural success rates, in spite of attempting CTO percutaneous coronary intervention (PCI) in increasingly complex patients and lesions .Yet the barriers to treatment for this group remain formidable and include sometimes long procedure duration and cost , perceptGiven that angiographic markers of complexity predict longer procedures with higher incurred costs, it may be that the higher complexity  causes a reflection on the prognostic benefit of the procedure that does not seem to defer non-CTO PCI . Yet it This series of commissioned articles aims to review the evidence base of CTO PCI, define the evolution of techniques with particular reference to the pathophysiology of the disease and describe how techniques have evolved to meet the challenges referred to above. It defines the role for pre-procedure planning in treating this complex lesion subset, describing the role for adjunctive imaging both in planning and in ensuring optimal procedural results. The chronicity of these lesions carry specific challenges and newer techniques for treating coronary calcium and ensuring both equipment delivery and optimum stent deployment are also covered.It is clear that success in the CTO PCI environment can no longer be claimed by individual, relatively small series, but should be viewed more in terms of growth in the overall percentage of CTO PCI patients. The challenge is to ensure that anatomical factors do not deter physicians from percutaneous revascularization where clinical indications support it.


Overcrowding in emergency departments is a global issue, which places pressure on the shrinking workforce and threatens the future of high quality, safe and effective care. Healthcare reforms aimed at tackling this crisis have focused primarily on structural changes, which alone do not deliver anticipated improvements in quality and performance. The purpose of this study was to identify workforce enablers for achieving whole systems urgent and emergency care delivery.n = 102); a qualitative survey (n = 48); and a review of literature and analysis of policy documents including care pathways and protocols.A multiple case study design framed around systems thinking was conducted in South East England across one Trust consisting of five hospitals, one community healthcare trust and one ambulance trust. Data sources included 14 clinical settings where upstream or downstream pinch points are likely to occur including discharge planning and rapid response teams; ten regional stakeholder events  contains supplementary material, which is available to authorized users. Overcrowding in emergency departments is a global issue, which places pressure on the shrinking workforce and threatens the future of high quality, safe and effective care –4. DespiUrgent and emergency care refers to the range of healthcare services available to people who need medical advice, diagnosis and/or treatment quickly and unexpectedly . The risPressures arising from increased workloads and limited resources are diminishing the desirability of careers in emergency medicine. This is exemplified by fewer practitioners choosing to pursue a career in emergency medicine citing poor working conditions, work-life balance, a target-driven culture, and the lack of 24-hour consultant support as reasons for their lack of desire to engage in this work . As a reWhole system approaches to urgent and emergency care have garnered attention as strategies to alleviate overcrowding in emergency departments (ED) , 8 but tHow do we solve the current workforce crisis in emergency departments creatively to promote sustainable transformational change?What should the urgent and emergency workforce of the future look like?A descriptive multiple case study design was used to clarify gaps and pinch points in the various contexts of the urgent and emergency care pathway across primary/community, secondary and tertiary settings. This design facilitates empirical investigation of phenomenon within real life contexts to answer ‘how’ and ‘why’ questions, especially when the boundaries between the phenomenon and the contexts are not evident . A multiData collection and analysis were informed by systems thinking which provides a rational process for mapping and understanding relationships to address complex issues in a holistic way. Checkland defines a system as a complex entity at the core of which is the concept of a whole that can adapt and survive within limits in a changing environment . The whoThis study was based on the concept that achieving transformational change in complex systems also requires attention to patterns that drive thinking and behavior in order to promote a sense of shared responsibility that mirrors ways of working among interdependent partners . SystemsData were collected from multiple sources using the fourth generation stakeholder evaluation approach . The metWhat is urgent and emergency care?What are the redesign, innovation and policy issues?What are the required standards?What are the required competences?What factors enable or inhibit these?What are service user perspectives on urgent care?Four methods were used to gather qualitative data to gain clear understanding of issues emerging in urgent and emergency care. Firstly, a review of evidence relating to urgent and emergency care delivery including care pathways and protocols was undertaken to understand international and national workforce implications. The review was guided by six questions:Competence was defined as acquiring and using evidence-based scientific and humanistic knowledge and skill in the application of therapeutic interventions in the practice setting .Understanding of urgent and emergency careUltimate purpose of urgent and emergency careHow purpose is achievedCurrent urgent and emergency care pathwaysPotential or future urgent care pathwaysEnablers and inhibitorsKey competences required for current and future integrated urgent and emergency carePerceived gaps in pathway competenceKey roles in urgent and emergency careWhat would happen in an effective integrated urgent and emergency care system and how effectiveness would be recognized? This specific question drew on the concept of ‘the miracle question’ from solution focused approaches to envisage options for achieving an effective system in the future .Other considerationsSecondly data were collected from ten regional stakeholder events held in South East England across one Trust consisting of five hospitals, one community healthcare trust and one ambulance trust. The events were widely publicized using both electronic and paper flyers which included the research questions. The stakeholder events were facilitated using a claims, concerns, and issues approach  to pave At each stakeholder event, discussion points and other verbal contributions were noted on separate flipcharts for each question to enable collaborative data analysis. Some participants gave accounts of their experience with or within the service to demonstrate the gaps and pinch points in the service and or in the workforce. These accounts were themed but also maintained as case examples , acute services (n = 10), ambulatory care (n = 13), residential and nursing homes (n = 6), ambulance services (n = 4), clinical commissioning groups (n = 3), service user groups (n = 16), voluntary sector workers (n = 3), social services and enablement services (n = 6) and Higher Education Institutes (n = 11).Participants in the study were urgent and emergency care stakeholders including representatives of service user groups. The 102 participants that attended stakeholder events organized across the region included representatives from primary/ community services (13), accident and emergency departments (n = 8), community and hospital pharmacists (n = 1), specialists and allied health professionals (n = 30), Ambulance staff/ paramedics (n = 1), public/patient groups (n = 2) and residential and nursing homes (n = 6).Forty-eight respondents completed the online survey that targeted underrepresented groups at the stakeholder events. These included general practitioners 111 urgent care telephone advice service; hospices; minor injuries units; mental health services; rapid response teams; integrated care24; and hospital at home.The multiple data sources facilitated triangulation, enhanced the validity and reliability of the case study and provided holistic understanding of existing challenges in the urgent and emergency service and workforce.Primary data analysis involved collaborative thematic analysis with participants at each stakeholder event to empower participants to co-create a shared purpose . CollaboThe research team used a similar process to generate themes from the literature review, qualitative online survey and process mapping activity. Themes from each of the four datasets were maintained separately during primary level data analysis to enable cross data consistency checks .The research team completed secondary level data analysis by triangulating themes from all datasets and synthesizing them in relation to broad system components , 27. TheThe data analysis process entailed distinguishing characteristics of a whole system approach to urgent and emergency care and developing a representative framework of system and workforce development enablers and outcomes. Data were consciously organized using systems assumptions, into enablers (inputs) and desired outputs for whole systems urgent and emergency care delivery . The synThemes from the miracle question about an ideal effective integrated urgent and emergency care system yielded the criteria for whole systems urgent and emergency care. Participants characterized an urgent and emergency care whole system as one that is safe, sustainable and person-centered; based on best evidence and practice standards; integrates health and social care; focuses on quality and safety rather than targets; is tailored to meet needs in the local population; and involves interdependent partners working together towards the same purpose. Additional file fragmented working without clinical systems leadership causing duplication and waste;a lack of any integrating competence framework to enable staff recruitment, development and retention across all contributing partners; anda lack of team approach to the competences needed to cope with urgent and emergency care demands across the health economy.Gaps and challenges identified in the current service informed system and specific workforce enablers, building on what works and envisioning what is required for whole systems urgent and emergency care delivery. Three overarching themes prominent in the process mapping gap analysis matrix emerged from all datasets:We hypothesized that whole system enablers identified across datasets have implications for workforce development at every level ranging from provider-user interfaces; career development across urgent and emergency care; systems leadership; human resource management through to infrastructure development; public information systems, and commissioning.There is a lack of integrated pathways and too many clinical commissioning groups to work with.Participants perceived commissioners to be the gatekeepers for a common strategy that models integrated working at the commissioning level and works to dismantle barriers that drive silos across the system particularly around the use of budgets and information in acute and primary care settings. One urgent care clinician commented:Additional file Recruitment has been a real problem for our trust. staff are moving away from the trust towards general practice. Staff need to have acute experience and know how the systems and processes work in both the community and hospital setting. I often feel that I could facilitate early discharge if a discussion was held between ourselves and the ward staff.Core challenges across the whole health economy were identified as both recruitment and the retention of staff and that these need to be addressed in a joined up way through system and specific workforce enablers. For example, a lead for a community healthcare team stated:Three specific workforce enablers emerged as most significant not only for achieving a whole system approach to workforce transformation, but also for addressing issues pertaining to staff recruitment and retention. These were: i) clinical systems leadership, ii) an integrated career and competence framework and iii) facilitators of work based learning.“Integrate experienced clinicians into the system. Management needs to be much better in an integrated system. Currently ridiculously fragmented” .At the moment there are many senior managers and I think their role and expectations should be reviewed. There always seems to be many meetings/discussions but there are few actions generated and these are not adhered to in a timely manner. There needs to be a greater emphasis on clinical skills and practice development so that new services/skills can be explored and supported in practice (emergency care nurse).Secondary analysis of data overwhelmingly indicated the need for a much stronger focus on leadership with less emphasis on management. Themes from all datasets denoted that clinical systems leadership would complement leadership for commissioning urgent and emergency care services. This is reflected in statements made by some of the participants:Clinical systems leadership is a concept we assigned to the leadership approach that drives integration across boundaries based on specialized clinical credibility working with shared purposes to break down silos and deliver person-centered, safe and effective care with continuity. Clinical systems leadership was linked to the ability to draw on expertise in a number of different areas to enable contributing partners to work together towards a shared purpose and to create a culture that values and retains staff. The required skill identified in the data encompasses: clinical expertise and credibility for a specific client group; consultancy functions that share expertise within the wider system; leadership for culture change; developing, improving and evaluating person centered care; and creating a learning culture that uses the workplace as the main resource for learning.There is a need to think productively, are the right resources in place, clear roles and responsibilities. Identify what skills and jobs could be done by administrative or healthcare support workers rather than removing a nurse or qualified healthcare professional from hands on care.Cross data analyses suggested that a single integrated career and competence framework would enable staff recruitment and retention and also empower staff to know how the systems and processes work in both the community and hospital settings. One emergency care doctor emphasized:Assess Treat (treat people appropriately and promptly for their urgent and emergency care needs within different contexts)SORT  people appropriately within or across the system and its different contexts in a timely way)Assess, Treat and SORT  constituted the single integrated career and competence framework we developed outlining key competences performed in any context by interdependent partners. Themes relating to competences required for current and future integrated urgent and emergency care from each of the datasets were triangulated to identify the key outcome competences. That is, what staff would be expected to do in the workplace underpinned by essential knowledge and understanding. We created three categories for the key competences to reflect the person’s journey through the urgent and emergency care pathway.The key competences were mapped against national competence frameworks identified in the literature for professional groups working across the urgent and emergency care system to validate the themes generated for the single integrated career and competence framework. Additional file A multidisciplinary career and competence framework for urgent and emergency care demonstrates whole systems working in managing the patient pathway and experience in any context - promoting an interdisciplinary team approach underpinned by shared risk and integrated information and finance systems.Case example 1 illustrates how a learning disabilities consultant undertaking a program to develop expertise in the functions of clinical systems leadership  works collaboratively across boundaries to ensure that a person with learning disabilities and complex needs receives appropriate care and avoids hospital admission. This case example also illustrates effective use of resources in place, and attributes of systems leadership with a focus on person centered, safe and effective care. Case example 1 was an account of the participant’s experience with the service shared at one of the stakeholder events.A nurse working with people with learning disabilities in the community and an aspiring clinical systems leader at the hospital have been corresponding for two weeks about a person with a learning disability and an autistic spectrum condition. The person had recently been discharged from hospital to a residential care home having had a fall and a fractured ankle. The community nurse contacted the hospital about the individual’s loss of skills and mobility over the last four months along with disturbances in behavior that did not appear to be mental health related. A closer review of the records indicated that the individual had experienced two admissions and three visits to the emergency department not quite triggering the learning disability repeated admission pathway (people with learning disabilities admitted through the accident and emergency department three times or more). Diagnostics also suggested a possible malignancy. The aspiring clinical systems leader linked the community nurse with an orthopedic consultant and the general practitioner via email, encouraging coordinated discussion about the individual, which led to swift conclusion regarding the possible diagnosis of cancer and further discussions about interventions for behavior problems and loss of skills. The individual did not require another emergency admission due in part to the collaborative practice across several organizational boundaries and the individual’s care being coordinated effectively.Case example 2 illustrates how the single career and competence framework can be used in everyday practice for diverse contexts and roles to facilitate work based learning and career development. Case example 2 was developed by the research team to illustrate how the Assess, Treat and SORT can be used to support career development.A community nurse working part of an integrated discharge team plays a vital role in preventing unnecessary hospital admissions by liaising with others to make sure that older frail people receive the care and treatment they require in a home setting. For example, pain management, treatment for urinary tract infections and end of life care planning, taking into account the individuals wish about their preferred place of death.Formerly an emergency care nurse, the community nurse in question uses the integrated career and competence framework to undertake a self-assessment and submit a portfolio of evidence to a local university in order to gain academic accreditation for prior learning and development in the workplace. The community nurse is able to pursue a blended Master of Science advanced practice program at the university tailored to development needs identified. By demonstrating advanced skills in clinical assessment, history taking and decision making in addition to a prescribing qualification, the community nurse gains 60 academic credits towards accreditation for prior experiential learning at advanced practitioner level.Teams from the different organizations involved are often very tribal in their behaviors, with a low level of trust. People often do not understand their colleague’s role. This is counterproductive and negatively impacts on team working. The patient experiences disjointed care. Suggest more joint training across organizations and multidisciplinary events to build trust and understanding.Facilitators of work based learning emerged as an essential enabler for supporting the urgent and emergency care workforce competence and career development while using the workplace as the main resource for learning and development. Evidence from the data suggested that facilitating learning in the workplace would enable role clarity and a team approach to the competences needed for urgent and emergency care demands across the various contexts. A community matron working with people with long term conditions observed:Workplace mentors and supervisors that facilitate learning, development and improvement in a holistic way embrace the integration remit across the system and meet the learning needs of multi-disciplinary teams aligned to the single integrated career and competence framework. Participants evoked that this can be achieved through rotation opportunities which enable staff to become familiar with the whole system, and the talents and contributions of interdependent partners.Whole systems approaches to tackle overcrowding and promote collaborative working to improve people’s experience and health outcomes are more compelling in an era of increased demand and finite budgets. The objective of this study was to identify workforce enablers for achieving whole systems urgent and emergency care. Aligning workforce planning and development with population healthcare needs is crucial but complex, especially in light of changing needs in an aging population that present with a complex range of mental and physical morbidities , 36. HowThe most consistent finding was the need for strong systems leadership capable of enabling the creative reshaping of urgent and emergency care services while coping with change. Systems leadership is often presumed to be the remit of commissioners of healthcare services  however Results of this study indicate that system redesign and successful implementation is facilitated through enabling the workforce to acquire competences needed to cope with complexity and changing models of care . In addiWorkplace facilitation spans a number of purposes including learning, development, improvement, inquiry, knowledge translation and innovation . ResultsThis study illuminates whole systems working which involves integrating all system elements including structures, processes and patterns that drive thinking and behavior in the workplace to achieve transformational change.The collaborative and inclusive approach used the study demonstrates a partnership drawing on providers’ and users’ experiences to achieve shared direction and valued outcomes. This approach is most likely to obtain and sustain positive change in the delivery of care.Nevertheless, it is probable that stakeholder events may have inhibited freedom of expression as opposed to user only groups. While this resulted in powerful case studies to illustrate an ideal system, the same drawback may have also influenced discussions with junior staff involved in delivering urgent and emergency care.In this study, participants agreed that whole systems urgent and emergency care allows for the design and implementation of care delivery models that meet complexity of population healthcare needs, reduce duplication and waste and improve healthcare outcomes and patients’ experiences. For this to be achieved emphasis needs to be placed on holistic changes in structures, processes and patterns of the urgent and emergency care system. Often overlooked, patterns that drive the thinking and behavior in the workplace directly impact on staff recruitment and retention and the overall effectiveness of the organization. These also need to be attended to for transformational change to be achieved and sustained. We recommend further work to refine and validate the integrated career and competence framework by testing competences against all key roles in different contexts across interdependent partners contributing to the system; and to identify standards for integrated facilitation in the workplace to grow the capacity of work based facilitators and ensure consistency in quality and effectiveness of this role.NHS, National Health Service; SORT, support discharge, organize admission, refer and/ or transfer; UK, United Kingdom


Somatic integration of synaptic inputs relies on the propagation of currents arising from sources across the dendritic tree. Whilst active processes strongly contribute to current flow in most neurons, understanding the passive backbone to transmission allows a better intuitive grasp of dendritic function; the results of Rall in highlighting the properties of cylindrical dendrites are of fWe have derived an asymptotic approximation to the voltage in dendrites with an arbitrary taper profile using the insight that voltage attenuation is substantially faster than radius change in realistic morphologies Figure . This reA particularly interesting implication of these results is that the optimal taper profile to proximally transmit maximum voltages can be found by variational calculus, matching results from non-parametric numerical optimisation which predicted a quadratic form for the diameter taper Figure  3]..3].


Open access journals provide an opportunity to read quality research articles through internet across the world. Concern has been shown as to the standard of articles published in open access journals and their peer review process but same has been refuted by a study of Björk and Solomon.[1] They have concluded that scientific impact of open access journal is now approaching that of subscription journals.In paediatric surgery, the impact of open access journals has not been evaluated presently but hopefully as they receive impact factor in future, this issue shall be addressed. There is encouraging trend towards addition of open access journals of paediatric surgery to international databases which in itself reflects quality of such publications. But unfortunately, most of the open access journals originate from developing countries. Few of these are “Electronic-only” publications. This takes care of cost of publication and therefore become economical and viable option on the longer run. The foremost issue is why journals from technologically advanced countries published by giants in the field of publications still charging huge amount both from the contributors as well as readers. The cost is huge not within the reach of researchers, students, residents etc from developing countries. This amounts to putting hurdles for researchers from developing world where the need of research is most. This gap is now being filled by open access journals and the number of manuscripts being sent to them and their quality has visibly improved. Same trend is apparent in our APSP Journal of Case Reports (AJCR). This is indexed with international databases and we hope to get impact factor soon. We have no conflict of interest as this is an official journal of The Association of Paediatric Surgeons of Pakistan (APSP). There are no subscription and publications charges thus researchers are encouraged to send their quality manuscripts for publication to this journal. Our peer review system further ensures that all submissions are seen by experts in the field to improve standard of the manuscript. We are thankful to all of our contributors and reviewers for their hard work.Source of Support: NilConflict of Interest: None declared


This article presents a historical review of the protein structure classification database CATH. Together with the SCOP database, CATH remains comprehensive and reasonably up-to-date with the now more than 100,000 protein structures in the PDB. We review the expansion of the CATH and SCOP resources to capture predicted domain structures in the genome sequence data and to provide information on the likely functions of proteins mediated by their constituent domains. The establishment of comprehensive function annotation resources has also meant that domain families can be functionally annotated allowing insights into functional divergence and evolution within protein families. •We present a historical review of the protein structure database CATH.•We review the expansion of the CATH and SCOP resources with sequence data and functional annotations.•How functional annotation resources allow insights into functional divergence and evolution within protein families. Several studies had shown the extent to which protein structures are conserved during evolution which suggested that 3D structure was a valuable fossil capturing the essential features of an evolutionary protein family and making it possible to identify even very remotely related proteins through similarities in their structures.The first protein structure, myoglobin, was solved in 1958 and for the following three decades the number of structures solved and deposited in the Protein Databank Although global structural characteristics (ie the folds of homologous proteins) are largely conserved during evolution The development of structure comparison algorithms by Rossmann and Argos Pioneering studies of groups of related proteins, by Chothia and Lesk Lesk and Chothia also published a seminal study on the relationship between sequence identity and structural similarity These studies prompted the question of whether other general trends could be gleaned from reviews of protein families. Furthermore, the concurrent expansion of the PDB and development of more robust techniques for comparing structurally distant homologues led several groups to begin classifications of protein families based on structure. The domain was the focus of these studies as it was clear this represented the primary unit of evolution and proteins evolved through duplication, shuffling and fusion of domain sequences in genomes Early structure comparison algorithms exploited rigid body algorithms to superimpose the structures based on the 3D coordinates and the methods struggled to achieve an optimal superimposition between distant homologues. Generally, they failed to converge on a solution where substantial insertions/deletions (indels) and changes in secondary structure orientations had occurred. Therefore in the late 1980s, more sophisticated approaches were explored  could easily be confirmed using pairwise algorithms like BLAST This was a considerable task but arguably more reliable than relying entirely on completely automated approaches. Over the last decade or more, much more sophisticated sequence comparison techniques have been developed that can confirm homology even in the midnight zone of sequence similarity (<20% sequence identity). These are discussed in more detail below.In 1997 the SSAP algorithm was modified to increase the speed for large scale comparisons within the PDB, by employing a filter that only allows comparison of proteins having sufficiently similar secondary structure arrangements and connectivity in their common structural core The SCOP classification was largely constructed using manual evaluation of domain relationships although available algorithms such as BLAST Both SCOP and CATH further classified the domain superfamilies and fold groups according to their architecture, where architecture describes the orientation of the secondary structure elements in 3D regardless of their connectivity. However, in CATH this was a formal level in the hierarchy whilst in SCOP architecture was simply an annotation. Finally domains were assigned to protein classes depending on the composition of secondary structure elements ie whether they were all-alpha, all-beta, or mixtures of alpha and beta see  SCOP use3ab-initio methods . This is because the linking regions between domains can be quite small and the domain interfaces quite large and complex, especially if one of the domains is dis-contiguous. Therefore, it is difficult to optimize parameters in a way that doesn't lead to under-chopping or over-chopping of large complex multi-domain proteins. The difficulty in capturing the heuristic rules defining domains in an algorithm is illustrated by the fact that an analyses of the performance of these methods, judged using a manually validated benchmark set, showed that all three approaches only agreed about 10% of the time and that frequently there were considerable differences in the boundaries assigned SCOP employs the same physical criteria in recognising domains by expert curation. Furthermore, a putative domain must be found to occur in at least two different independent contexts ie with different domain partners. This means that some protein regions deemed to be domains in CATH are not recognized as such by SCOP until additional data confirms the existence of this domain fused to different domain partners.In 1995 both CATH and SCOP publicly launched their classifications via the web 4Perhaps the most interesting revelation to emerge from the structural classification data was the highly uneven distribution observed in the populations of the fold groups. In 1994 Orengo, Jones and Thornton reported the existence of ten ‘superfolds’ accounting for nearly 50% of all domain relatives in CATH Based on the number of diverse sequence families found across the SCOP classification and the proportion of all known sequence data that this represented, Chothia postulated that there could be fewer than 1000 fold groups in nature In fact these predictions appear to have been largely borne out by the current data. Twenty years on, there are still only 1300 folds identified in CATH, and sensitive structure prediction tools suggest that CATH and SCOP capture nearly 80% of all protein domains in completed genomes with the remaining 20% being largely membrane associated domains which are likely to adopt relatively few diverse structural arrangements because of the physical constraints imposed by their location. The remaining sequences suggest highly disordered proteins that are not expected to adopt globular folds.The structural classification data and large scale comparisons of domain structures also revealed novel folding motifs  common to a large proportion of alpha–beta domain superfamilies in which structures comprise a central antiparallel beta-sheet covered by a layer of alpha-helices  a hypothesis that had been speculated as a ‘russian doll effect’ in the original CATH classification Development of faster structural comparison algorithms like GRATH 5The international genome initiatives which started in the late 1990s and exploited rapid sequencing techniques, enabled the completion of the human genome by the millennium, and resulted in an explosion of sequence data by the turn of the century. This expansion of the sequence data combined with much more sensitive tools for recognizing sequence similarities prompted the recruitment of sequence relatives into the domain superfamilies of SCOP and CATH. Both resources exploited powerful sequence profiles – known as Hidden Markov Models (HMMs) – which were built from multiple alignments of sequence clusters in domain superfamilies and used to recognize domain relatives in the genome sequences. Two sister resources were established – Gene3D These strategies brought about an ∼100-fold increase in the number of domains assigned to CATH and SCOP allowing more detailed analyses of evolutionary relationships and in particular an understanding of the divergence of sequences and functions within particular superfamilies (discussed more below). Currently more than 50 million sequences are assigned to CATH superfamilies in Gene3D. SUPERFAMILY which has explicitly incorporated completed genome data not yet deposited in public repositories like UniProt and ENSEMBL, has more than 40 million sequences from 2500 completed genomes. This data is likely to expand further in the near future as the metagenome projects bring in millions more relatives from species in diverse environments from around the globe.By recognizing CATH or SCOP domains within protein sequences it was possible to trace the emergence of novel proteins resulting from different domain fusions or fissions. For example, Vogel and Chothia examined changes in domain partnerships in proteins linked to the immunoglobulin superfamily. In worm, expansions in multi-domain architectures were linked to the expansion of structural proteins whilst in fly, expansions involving related domains enhanced the immune system repertoire 6The expansion of CATH superfamilies with sequence data considerably increased the amount of functional data too, allowing large scale studies of the divergence of function within superfamilies during evolution. These studies showed that whilst relatives in most superfamilies shared a common function, in the most highly populated superfamilies considerable divergence of sequence and function had occurred. A detailed study of 31 such diverse superfamilies revealed the molecular mechanisms by which functions had changed Studies of enzyme superfamilies revealed that changes in function were usually associated with variations in the substrate specificity. Changes in chemistry were much less frequent presumably because it is harder to engineer a novel chemistry than to alter the binding site and change the compound on which that chemistry is performed More recent collaborations between the Thornton and Orengo groups have led to the establishment of a new resource, FunTree FunTree enabled much more comprehensive studies of functional divergence in domain superfamilies and confirmed the previously observed trends of conservation of chemistry between parent and child nodes in the phylogenetic tree but also highlighted frequent divergence in substrate specificity within some promiscuous enzyme superfamiles. However, significant changes in chemistry can still occur As regards the structural mechanisms mediating functional change, analyses of some structurally and functionally divergent CATH superfamilies revealed substantial insertion of residues often resulting in additional secondary structural features packed against the common structural core of the domain and appearing as embellishments to that highly conserved core. In some large CATH superfamilies, relatives differ in size by three-fold in the number of residues or more 7More recently, the extreme divergence of functional properties of relatives in some highly populated CATH superfamilies prompted the development of protocols to sub-classify superfamilies into functional families . Comparisons of interfaces across superfamilies showed that functionally diverse relatives were exploiting different surface patches on the structure ie distinct sites, depending on their interaction partner, and that paralogues shared few common interactors. However, quite frequently there was one location that was more frequently exploited by diverse paralogues Recent analyses of changes in catalytic residues in different functional families across 101 well annotated CATH enzyme superfamilies showed that in the majority of superfamilies (∼70%) at least two FunFams had significant differences in their catalytic machineries . Unsurprisingly, most of the time these led to changes in the chemistries of the relatives or the substrates being acted upon. However, in 25% of the cases examined the same chemistry was associated with completely different catalytic machineries. This may be a consequence of evolutionary drift from a common ancestor with a particular function, resulting in modified efficiency in one relative which is then compensated by further mutations to optimize the physico-chemical features of the active site 8The SCOP and CATH classifications organize the 3D structure of proteins into evolutionary classifications that have enabled detailed studies of the molecular mechanisms by which new protein structures and functions evolve. The sequence patterns and fold libraries that they provide have enabled prediction of structural relatives thereby providing structural annotations for more than 50 million domain sequences, available on their sister sites  and in InterPro Although ∼20–25% of domain sequences in the genomes do not currently map to any structural superfamilies in CATH or SCOP, the analyses of structures solved by the structural genomics initiatives in the States – which targeted structurally uncharacterized domain families in Pfam for structural determination – showed that once the structures of these superfamilies had been solved they revealed a structural or evolutionary relationship with an existing fold group or superfamily in SCOP or CATH. In fact, nearly 98% of all new structures deposited in the PDB can be classified in an existing CATH superfamily Over the last few years collaborations between SCOP and CATH have led to mappings between these resources that help to confirm detection of very remote homologues


After publication of the original article  it was b‘The statements presented in this publication are solely the responsibility of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee’.Also, author Joann Sorra was incorrectly included as Joanna Sorra. The correct spelling of Joann Sorra’s name is included in the author list of this erratum.


The Continual Reassessment Method (CRM) is not widely used in early phase dose finding trials partly because the logistics of development and implementation are perceived as complex and time consuming. Details are presented of the steps involved when designing such a trial using an adaptation of a Bayesian CRM calibration algorithm proposed by Cheung .In addition to clinician centred parameters including target toxicity probability and number of test doses, the Bayesian CRM requires specification of the prior probability of toxicity associated with each of the test doses and the prior SD of the single model parameter. Cheung’s simple pragmatic approach is used to aid selection of these parameters.Competing designs are assessed in terms of risk-adjusted accuracy and trial specific requirements including the mean number of patients treated above the maximum tolerated dose. Performance measures are estimated by Monte Carlo simulation across a range of scenarios chosen solely upon the target toxicity level and the number of test doses.We demonstrate that following this pragmatic approach to CRM design calibration, design of CRM trials need not be overly complex or time-consuming.


The external validity of RCTs, which provides evidence for major clinical guidelines, may be questioned if they are not representative of real-life populations in primary care.11–15 In the 2007 study by Travers et al, only 4% (range 0–36%) of participants with asthma in a population-based survey met the eligibility criteria to be included in 17 major RCTs cited in the GINA guidelines.14 The same study found that only 6% (range 0–43%) of participants receiving asthma treatment also met the eligibility criteria. The proportion of patients with asthma from primary care settings that would be eligible for the major RCTs is unknown. If the proportion is similar to that found in the study by Travis et al., then the generalisability of the conclusions and the clinical relevance of major RCTs may be questionable, and they have not been improved in the past decade. There is a need to explore the external validity of pharmacological RCTs in primary care populations. The UNLOCK (Uncovering and Noting Long-Term Outcomes in COPD and asthma to enhance knowledge) project15 of the International Primary Care Respiratory Group (IPCRG) covers a broad primary care population that may help clarify the external validity of these RCTs.There are concerns that current asthma treatment is based on research with subjects who are not representative of the patients seen in clinical practice.The aim of this study is to determine whether the inclusion criteria for patients with asthma in the major RTCs supporting GINA guidelines are representative of real-life primary care populations with asthma. The study will address the following research questions:What proportion of patients in primary care would be eligible for the major RCTs assessing patients at treatment step two heading for step three?What are the clinical characteristics of these patients when compared with participants in major RCT studies?1–8 The management and treatment of patients with asthma in primary care is a challenge, and many patients still suffer from poor asthma control.2 The major international clinical guidelines for the prevention and management of asthma are influenced by the empirical evidence and conclusions of RCTs.9–14 However, RCTs tend to be highly selective in terms of inclusion and exclusion criteria for people with asthma and may under-represent primary care populations with asthma. Smokers, for example, are usually excluded from registration RCTs assessing inhaled corticosteroids (ICS), as smoking is known to reduce the efficacy of ICS.16 Other common exclusion criteria are pregnancy, lactation, elderly patients and other chronic diseases such as ischaemic heart disease. A common inclusion criterion is a bronchodilator FEV1 reversibility of 12 or 15%, which is not a frequent clinical sign in real-life asthma patients, and in the Travers study, 71 (or 76%) of participants with asthma were excluded.14Asthma is a highly prevalent disease worldwide with variability and a large range of phenotypes.17 The assessment of the external validity of asthma RCTs is therefore needed to better understand the clinical relevance of their conclusions. There should be discussion on the need for effective studies, pragmatic trials and observational studies, as a complement to RCTs, to evaluate treatment outcomes in real-life clinical settings including the whole asthma population. The main weakness of these studies might be a lower internal validity, which needs to be addressed in the design of the studies. When developing guideline recommendations in the future, data from both efficacy and effectiveness studies should be evaluated with the strengths and weaknesses given.18RCTs are important in establishing the efficacy and short-term safety of new therapies, but there are limitations in evaluation of effectiveness of the therapies in the real world.16–20 Previous findings suggest that the level of representation of the population with asthma14 and chronic obstructive pulmonary disease (COPD)13 in RCTs may be lower than desirable. This study can inform not only the development of future clinical practice guidelines17–20 but also the way asthma clinical trials are being designed and implemented.10 The study will tell us more about the patients who are not eligible for these major RCTs, and it may also provide new insights into why the control of asthma in many patients does not appear to improve in spite of the implementation of the treatment strategies that are recommended in guidelines.This study will provide estimates of the proportion of real-life primary care populations that are eligible for RCTs. It will also present descriptive characteristics of primary care patients compared with patients included in RCTs. This will present relevant information for the adequacy and use of GINA and other major guidelines in primary health-care settings.The study will use an observational design for comparing baseline characteristics of asthma patients in primary care databases with the inclusion criteria in the pharmacological RCTs that support major international guidelines .Data collection will involve two steps:Step one will identify the major relevant RCTs used in GINA guidelines.Step two will identify the primary care data sets that contain the required variables to assess eligibility for participation in the major RCTs.In step one, a Systematic Review focusing the search on selected asthma international guidelines  will be conducted in order to identify all studies that fit the following criteria:Randomised controlled clinical trialPharmacological treatment at GINA management step 2 heading for step 3n>400RCT sample size Other criteria 21 statement guidelines and follow the steps identified in The systematic review will follow the PRISMAIn step two, members of the IPCRG UNLOCK group will be invited to participate in the study with primary care data sets that include the variables listed in Participants identified in the data sets will remain anonymous. Patient confidentiality will be assured in the collection and merging of the data sets.Data will be analysed according the defined criteria for the identification of RCTs. Statistical analysis of the data sets will provide summary descriptive statistics, means, measures of dispersion and proportions. The statistical analysis will focus on group classification values, and no individual statistical values will be computed or revealed.All included data sets will require approval by local primary care research ethics committees.


The lack of clinical data for orphan drugs and the development of “precision medicines” or advanced therapies have required a new regulatory approach to guarantee a marketing authorization for new and innovative medicines.What is actually changing in the scenario is the way Agencies are managing the regulatory procedures to ensure a rapid access to treatment for patients with unmet medical needs.In the last few years EMA and National Agencies have provided a lot of scientific advices (SA) to companies and applicants about orphan designation, CTs design, marketing authorisation procedures and HTA evaluations.Currently the global scenario is already changing as we are issuing licenses for marketing authorization under exceptional circumstances and conditional marketing authorizations. The legislative framework is also changing with the new Pharmacovigilance Directive and the new Regulation on Clinical Trials entering into force progressively by 2015.The new Pharmacovigilance Legislation supports a Progressive Patient Access Scheme  approach by expanding EMA authority to request mandatorily to Applicants a post-marketing evaluation of effectiveness in addition to safety.The basic principles of PPAS approaches are facilitating early access to an early medicine approval, by acknowledging and managing uncertainty about favourable and unfavourable effects. The result will be achieved through the conduction of optimised RCTs, the monitoring of risk-based SA and the harmonisation of RCTs platforms.Lots of effort is needed by everyone through a new level of cooperation, in particular regulators, companies and the CROs need to go down to patient level in order to evaluate how the trial is proceeding and by avoiding complex policies.Moreover, patients have to accept a certain level of uncertainty as the clinical studies are not completed and Clinical Trials investigators need a continuous talking to patients during the drug development to ensure the higher level of achievable safety.A successful PPAS pathway depends on the willingness of patients, regulators, health-care providers and payers to accept a greater level of uncertainty using the new medicine in the expectation of an improved benefit risk profile.Furthermore, PPAS approach could facilitate a more open and timely strong scientific dialogue and significant cooperation among stakeholders and a time reduction to full market approval resulting into a possible impact reduction on the overall cost of development.


Health systems around the world are grappling with the difficult issue of how to allocate scare healthcare resources. Within Europe many different approaches to healthcare resource allocation exist, but it is clear that the formal techniques of cost-effectiveness analysis are becoming increasingly important. This presentation will first address the fundamental economic principles of scarcity and opportunity cost, before looking at how different European systems are attempting to address the economic challenge of providing healthcare for their population from a limited budget. The presentation will go on to consider general issues in health economic evaluation that are likely important for clinical community focused on HIV treatment: appropriate comparator treatments for defining opportunity cost, patient heterogeneity and the potential for personalized/stratified medicine to control costs and target treatment appropriately.


The devastating toll of the Ebola epidemic in West Africa necessitates considerations of new approaches to research into new prevention technologies and treatments for Ebola Virus Disease (EVD). Research must be planned and delivered in consultation with civil society from the epicentre to prevent mistrust and misunderstanding. Ethical considerations include development of local research and regulatory capacity; negotiating the standard of prevention packages for research participants, including healthcare workers; and strengthening health systems in developing countries to ensure effective response to future EVD outbreaks in the region. Also, strategic consultation with local communities is an ethical imperative for EVD research, particularly where there is potential for differential access to prevention and care packages between trial staff and local hospital staff. The increasing incidence of cross-border infection exemplified by case detection in Nigeria, Mali, Senegal, England, United States and Spain, further necessitates consideration of new approaches to the evaluation and distribution of new treatment and prevention technologies. Despite possible remission of EVD symptoms following early detection and aggressive supportive care, mortality reported in the current epidemic has been estimated to be 73%  with morThe high case fatality may be connected to poor medical management of patients with EVD . ProvisiDevelopment of EVD treatment drugs and vaccines is very important, but glaringly, development of local capacity to provide care and support for patients with EVD is equally essential. Accordingly we will also address issues of local capacity in this paper, which will discuss and identify significant ethical considerations when planning the design and implementation of clinical trials for EVD treatment drugs and vaccines.Phase I trials for anti-EVD vaccines and therapeutics should happen in developed countries as is the norm with other drug and vaccine development process. This is because of the need to ensure optimum standards of clinical care and patients’ monitoring during phase I trials while establishing baseline safety data. Phase II trials however may be conducted in developing countries with EVD outbreaks. This should not preclude efforts to build local capacity in Africa to conduct phase I clinical trials. Kanapathipilla et al  proposedFor EVD vaccine research, Kanapathipilla et al  proposedUnfortunately, countries affected by EVD in West, East and Central Africa have grossly inadequate health infrastructure and do not have a large pool of personnel with competency to conduct clinical trials . In addiWhile most if not all of the EVD clinical trials protocols for treatment therapies and vaccine are developed primarily by researchers in the developed countries, this research will be conducted in collaboration with partners in the local settings. For EVD treatment research, health care workers will be actively engaged with drug administration and data collection. Also, healthcare workers are to be targeted as study participants for EVD vaccine research due to their heightened risk for contracting EVD . It is tFor healthcare workers as care providers, the standard of prevention package should include providing effective personal protective equipment (PPE) and implementing evidence-based standardised protocols regarding working conditions . There is evidence that suggests a need to improve the quality of PPE  as the cIn addition, due consideration should be given to the PPE requirements of those who wear prescription glasses and the use of fluid resistant particulate respirators when carrying out procedures that could cause aerolisation of infectious particles . While EFurthermore, participants and researchers will need to be carefully prepared to deal with fever that could arise as a complication of EVD vaccine research. Fever is a common vaccination side effect and, not unexpectedly, has been seen in a small number of participants in the human safety trials of one of the candidate Ebola vaccines . Fever iAs healthcare workers face increased risk of Ebola exposure and infection in their daily lives, it is also likely that some healthcare workers who volunteer for the EVD vaccine trials will acquire EVD. This raises the issues of the standard of care for EVD trial participants who become infected. The long-standing debate on what constitutes appropriate standard of care in resource constrained settings  has onceThe standard of care package for trial participants will need to be carefully negotiated to optimise care not just for participants but also for their local communities. In the context of HIV prevention trials, negotiation of standard of care packages has also been proposed, especially in situations where the standard of care between developing and developed countries differ significantly, and where the institution of international gold standard of practice may involve differing standard of care between research participants and other community members . DiscussA further ethical imperative for trial conduct in countries with EVD epidemics hosting EVD research is the need to ensure technology transfers. It is very clear that the development of EVD therapeutics and vaccines can no longer be delayed. The corollary of this is that research teams need to think about how to develop not only the infrastructure but also the human and administrative capacities in proposed research sites to facilitate the conduct of the required phase II and III trials. There is a need for structured supportive systems that promote local capacity building for research staff in Ebola-affected countries in ways that enable them to design and implement future research studies that can address local EVD containment. Unfortunately, the lion's share of the funding for research on Ebola is currently spent in developed countries outside Africa, with very little focus on building the capacity of researchers in affected region been able to lead Ebola research initiatives . This paThe ethical complexities of conducting clinical trials during epidemics of such magnitude as the current West Africa outbreak make it imperative that decisions about compassionate access for therapy and clinical trial design for EVD therapeutics and vaccines are made in consultation with affected communities, including non-medical members of civil society. Building shared understandings of the epidemic and research strategies to help affected people and communities are critical to the success of research and access programs, making the involvement of civil society in EVD research planning and implementation crucial.In an epidemic setting where the prospect for compassionate access to new interventions is possible, decisions about the conduct of clinical trials of such interventions has to be weighed against compassionate access for those infected or at high risk of infection. Compassionate access is important for humanitarian reasons, and it may also assist with gaining compliance with public health measures. Access to an experimental vaccine should however be based on defined clinical criteria that allow for systematic data collection, without preferential treatment for people with particular roles in society, in order to avoid entrenching social inequalities .Compassionate access to experimental therapeutics and vaccines may however deplete the supply of experimental interventions and complicate evaluative processes, as patient deaths or recoveries may be wrongly attributed to the experimental substances. This and other possible challenges with evaluation of the efficacy of potential EVD therapeutics and vaccines should not preclude access of citizens in a country where EVD therapeutics and vaccines clinical trials are been conducted to compassionate therapy.In a health crisis like that been currently experienced with EVD in West Africa, civil society consultation may sound like an unaffordable luxury. The decisions that need to be made over the following months about how to distribute and test experimental therapeutics and vaccines in West Africa will necessarily involve complex choices based on values, however.Without meaningful input from civil society, and strong support from the media for disseminating accurate and unbiased information, there is the risk that EVD therapeutics and vaccine research and development could exacerbate social inequalities and breed social unrest. Perceptions about social injustice could arise from differential access of trial participants and trial support staff to prevention and care packages that dichotomise the populace.Decisions therefore need to be made with communities on research design and implementation plans including participant recruitment process, whether or not some communities are too vulnerable to participate, and how to ensure communication of key concepts to community members who participate in clinical research. The decision-making process should promote collaboration between researchers and community members as invested stakeholders in the management and control of the EVD epidemic. Dialogue between researchers and communities should therefore be bidirectional and continuous up till the point of research result dissemination. Community-research partnerships should be the ultimate goal of the community engagement process for EVD therapeutics and vaccine clinical research programmes. The Good Participatory Practice Guidelines  developeDevelopment of effective EVD treatment drugs and vaccines must be a global priority. Prevention however cannot be the only strategy for combatting this disease. Pictures and reports from countries affected by the EVD have shocked the world, with men, women and children suffering and dying in unspeakable conditions that attest to the parlous state of health infrastructure in areas stricken by the disease. The social and economic effects of the epidemic will further delay the development of infrastructure that is urgently needed to provide decent care to people in these countries. Strengthening the health systems of countries with low GDP needs to be given global priority while effective EVD therapies are been researched and developed. The next epidemic may hit another region in Africa outside the current know zones of the epidemic. The world cannot afford a repeat of the current EVD epidemic we are witnessing.


Research into correlates and determinants  of fatigue has burgeoned in the past two decades. However the link between cortical activity and muscle force generation on fatigue that develops during exercise is not very well understood. While there is extensive evidence suggesting that the central nervous system can contribute to the inability of a human being to sustain a motor task, some questions are unsolved. Is fatigue a sensed variable? Could substantial progress in neurophysiological techniques have additional benefits in the understanding of fatigue? What have we learned and what happens next? Answers require likely the combined insights not only from physiologists, but of neuroscientists and psychologists. Recent research in this area presents three trends providing current interests and opinions in the field.The first issue concerns the fatigue state with respect to changes in motor performance. The picture of fatigue that emerges is the conscious perception of a sensation of fatigue according to the phenotypic traits of the individuals mediated by environment and culture  with sufficient ecological validity Mauger,  is a rapAdvances in functional neuroimaging techniques of the human brain with behavioral outcomes, such as electroencephalography (EEG) and near-infrared spectroscopy (NIRS), helped to generate first valuable data in human exercise research. Increased muscle recruitment as revealed by electromyographic activity was accompanied by a higher brain cortical activity (measured by EEG) localized mainly in the primary motor cortices during unilateral isometric knee extensions . The PFC involved in motivational and decision-making processes is an important candidate for acting as relay station in the central fatigue related network regulating central command. Development of fatigue at the highest force output during intermittent isometric upper limb contractions was attributed to reduced muscle oxygen availability rather than impaired prefrontal oxygenation  have also gained popularity owing to its potential to explore the neural processes underlying motor functions Mauger, . Recent Investigating the post-exercise recovery strategies could shed light on the contributions of the brain into the control of muscle force with fatigue development. Regarding the post-exercise recovery period, little or no data are available concerning central processes of performance  to understand cortical brain function during and after exercise in healthy humans should guide our future works.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.


Sibling recurrence data from the Baby Siblings Research Consortium (BSRC) recapitulate results from very large clinical family studies that demonstrate the absence of the Carter effect and provide clarification of the nature of the female protective effect in ASD. This legacy prospective data collection confirmed marked differences in the proportions of males versus females who lie along deviant trajectories of social development in the setting of inherited liability to autism—a phenomenon which defines the female protective effect—and demonstrate that among affected children, sex differences are modest and homologous to those observed among non-ASD children. I read with great interest the report and analysis of the extensive collection of data by the Baby Siblings Research Consortium regarding early sex differences . Given tnot observed for ASD in the Baby Siblings Research Consortium (BSRC) sample. But the absence of the Carter effect is not the same as the absence of a female protective effect.What the data suggested, replicating what has actually been previously reported by numerous prior studies , 3, is tThe manuscript describes the BSRC observation that across a number of developmental competencies, modest sex differences were observed, and the discrepancy between boys and girls with ASD was not different in magnitude from that between typically developing boys and girls. The authors conclude that therefore sex differences were “not autism-specific.” Examining males and females within the category of the disease-of-interest is an important exercise in understanding sex differences, but there can be profound ASD-specific sex effects on a disease that render sex differences among affected subjects relatively minor and indistinguishable from those differentiating typical boys and girls. Conduct disorder provides an excellent example—the differences between males and females who meet diagnostic criteria are minimal (by definition) and yet males are six times more likely to be affected than females. within any subject group was dwarfed by the magnitude of difference across groups (ASD versus non-ASD). Since the “quantum leap” from typicality to clinical abnormality  occurred over three times more commonly for male siblings than for female siblings (this was the second major clue generated by the study data), the data actually represent a remarkable manifestation of sex-specific modulation of inherited liability, which is the fundamental nature of the so-called female protective effect. The refocusing of the problem on contrasts across groups rather than within groups is represented by comparing the arrows and relative sample sizes in Fig. In the case of ASD, the first major clue generated by these data was that the magnitude of sex difference for any given trait In prior published work, we have presented evidence for the manner in which a female protective effect might operate in the absence of the Carter effect, essentially via a categorical mechanism of protection by which most females are protected from most forms of ASD , 7–9. Thdefines the female protective effect—and demonstrate that among affected children, sex differences are modest and homologous to those observed among non-ASD children.The BSRC data recapitulate results from very large clinical family studies that demonstrate the absence of the Carter effect and provide clarification of the nature of the female protective effect in ASD. The prospective data collection confirmed marked differences in the proportions of males versus females who lie along deviant trajectories of social development in the setting of inherited  liability to autism—a phenomenon which


The evolution of intrauterine development, vivipary, and placentation in eutherian mammals has introduced new possibilities and constraints in the regulation of neural plasticity and development which promote neural function that is adaptive to the environment that a developing brain is likely to encounter in the future. A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time . The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain. In conjunction with genomic imprinting, it also provides a template to integrate epigenetic information from both maternal and paternal lineages. Placentation also hands ultimate control of genomic imprinting and intergenerational epigenetic information transfer to the matriline as epigenetic markers undergo erasure and reprogramming in the developing oocyte. These developments, in conjunction with an expanded neocortex, provide a unique evolutionary template by which matrilineal transfer of maternal care, resources, and culture can be used to promote brain development and infant survival.  Two major innovations have contributed to the evolutionary success of mammals. The first is the evolution of a foetally derived placenta which enables the foetus to influence its own destiny, whilst placing a considerable burden in terms of time and energy investment on an expectant mother. Hormonal cues provided by the developing foetus influence maternal neural function, increase maternal food consumption to compensate for increased energetic costs , suppresThe mammalian brain has undergone profound changes during its evolution. The huge expansion of the neocortex especially in primates has facilitated a shift in the complexity of social interactions and in primates complex social cues replace changes in hormonal states to promote maternal and sexual responses. Parturition is not required to initiate maternal behaviour which is therefore displayed towards a range of offspring in a social group and sexual interactions may occur out of oestrus and are used to reinforce social attachment. The most important phases of neocortical development and socialisation occur during periods of maternal attachment, among stable groups of females that extend over more than one generation. There are often complex social hierarchies within these groups and social rank is often inherited matrilineally from the mother .The developing mammalian brain can demonstrate remarkable plastic and adaptive responses many of which serve to adapt the brain to an environment that it will encounter when mature. This may account for the ease in which mammals have undergone adaptive radiation into a wide range of environmental niches, where evolution of the brain and neuronal phenotype has paralleled adaptations in physical structure. In this review we focus on the importance of a number of mechanisms that contribute to this and emphasise the importance of the matriline in these mechanistic processes. We also suggest that failure in these processes can result in the induction of deleterious neural and peripheral phenotypes that cannot be viewed as traditionally pathological but are phenotypes which are adaptive to the environmental conditions with which an individual or its mother interacted during early development. Subsequent shifts in environmental conditions during an organism's later development may leave it with a poorly environmentally adaptive phenotype and a propensity for health problems.The hypothesis of predictive adaptive responses or plasticity (PAR) was originally developed at a whole organism level to provide a mechanistic framework by which a developing organism can attempt to predict and modify its developmental phenotype to accurately match the environment that it will encounter when mature. It also incorporated a range of ideas that attempted to explain why early life experiences are associated with an increased risk of disease in later life, especially in contemporary human societies –23. TherMicrotus pennsylvanicus) born in late summer and early autumn have much thicker coats than those born in the spring. The proximal cue for this is a reduction in day length, which is transmitted to the developing vole in utero via melatonin signalling originating in the mother [A range of predictive adaptive responses involving the brain have been described in a number of mammalian species. One of the simplest and earliest related to the observation that vole pups  which provides a unique template by which a mother can transmit environmental information to her developing foetus and her potential grandchildren. The placenta is produced by the developing foetus and provides a mechanism by which it can attempt to control the physiology and neural function of its mother to its own advantage. Progesterone secreted by the placenta suppresses sexual activity , 3; its Placental hormones also prime the oxytocin system in anticipation of parturition where oxytocin release is required to support uterine contractions, milk ejection, and maternal behaviour in the mother , 6 and t in utero via placentation or postnatally via lactation and efficient maternal care [The developing foetus begins to exert considerable leverage on the neural function of its maternal hypothalamus during early placental development at the same time as it develops a hypothalamus of its own , 47, 48.nal care , 47, 48.Genomic imprinting refers to a form of monoallelic gene expression whereby the expression of an allele depends on its parental origin. The fact that genomic imprinting is absent in egg laying mammals and the fact that there are only 6 or so recorded imprinted genes in marsupials but around 150 imprinted genes in eutherian mammals have driven the development of over 14 interesting theories that explain their existence . Most ofPeg3) has provided a range of evidence that supports the role of imprinted genes in the development of coadapted responses between the hypothalamus and placenta. The Peg3 gene can be inactivated in the maternal hypothalamus but not the placenta or hypothalamus of offspring or be functional in the maternal hypothalamus but inactivated in the hypothalamus or placenta of offspring. Both of these paradigms produce remarkably similar deficits in hypothalamic cell number, maternal behaviour, and impaired suckling, which leads to impaired growth, onset of puberty, and reproduction [Many imprinted genes are coexpressed in the developing hypothalamus and placenta, and a range of studies using mice with an inactivated paternally expressed gene 3 , which are thought to be important for the regulation of monoallelic gene expression and disruption to these can be associated with Prader-Willi and Angelman's syndrome . ImprintThe development of the brain is by definition a complex epigenetic process; neural systems are designed to respond to environmental changes as the interactions of over a trillion synaptic connections both are activity dependent and can be subjected to epigenetic modification. This occurs throughout the life of an individual but at key stages of development, epigenetic modification of neural function is under disproportionate control of the matriline. The erasure and reprogramming of the epigenetic landscape in the developing oocyte, interaction of the developing brain and placenta with environmental cues, the ability of a developing brain to accurately assess present conditions and accurately anticipate the future, and programming of the postpartum brain via efficient maternal care and lactation are all disproportionately matrilineal processes. No two brains are ever alike and even monozygotic twins exhibit increasing differences in behaviour and predisposition to psychiatric disorders as they age , 55 whicThe evolution of paternally derived intergenerational effects on offspring fitness and phenotype may suggest one further mechanism by which adaptive traits can be passed rapidly through an expanding population. Beneficial genetic variations and epigenetic modifications of monoallelically paternally expressed genes will spread far more rapidly through a population than those of monoallelically expressed maternally expressed genes. This is because mammals typically have fewer ancestral fathers than mothers as in males freed from the energetic burden of placentation reproductive success is based on competing to impregnate as many females as possible. This means that many low status males fail to breed and yet high status males often have large numbers of offspring. In populations that are moving into novel environments, who then subsequently undergo a rapid expansion this reproductive asymmetry coupled with the evolution of paternally expressed  gene expression provides an elegant mechanism to rapidly distribute traits that are adaptive to neural function. Adaptive gene variants and epigenetic modifications of paternally expressed genes will spread extremely rapidly in such rapidly expanding population, especially in circumstances where there are few ancestral or founding fathers. This is an important adaptive trait when populations are moving into new environmental niches. There are animal examples of this gender asymmetry of ancestral influences but one rare but illustrative human example of this process relates to the amazing fecundity of Genghis Khan who was thought to have sired over 1,500 children. This productivity was also replicated by his sons and grandsons. As a consequence there are now over 16 million men in Asia who can trace their Y chromosome lineage to an extremely small number of reproductively successful men living in the 12 and 13th centuries .In circumstances where an organism's early life environment provides accurate predictive cues to the environmental conditions prevailing when adult, the ability of the developing foetal and neonatal mammalian brain to adjust its development to optimally match its function to the requirements of its adult environment confers profound advantages in terms of survival and reproductive fitness. One evolutionary development that elegantly facilitates this process in eutherian mammals is the development of a foetally derived placenta, by which the foetus can attempt to control its own destiny and hormonally regulate the maternal hypothalamus to leverage maternal resources for its own benefit. This is a unique situation that requires the interaction and coadaptation of three matrilineal generations and hence genomes interacting in one organism at the same time . This provides a template by which a mother can transmit adaptive information concerning present and potential future environmental conditions to the developing foetal brain over an extended period. When combined with the evolution of imprinted genes and disproportionate maternal control over the mechanisms of epigenetic inheritance, this provides a mechanism to ensure intergenerational coadaptation of the maternal hypothalamus, developing brain, and placenta, integrate potential maternal and paternal interests, and promote the optimal allocation of maternal resources and transfer of matrilineal cultural influences. In circumstances either where the early environment provides inaccurate cues to the environmental conditions prevailing when adult due to rapid environmental change or when disruptions to normal neural development occur, the mismatch between the environmental predictions made during early development and subsequent reality may mean that an organism may have a poorly adapted phenotype to its adult environment which may predispose it to health problems. An appreciation of these underlying evolutionary salient processes may provide a novel perspective on the casual mechanisms of a range of health problems. The concept of a brain that is not pathological in the classical sense but it is simply mismatched to its environment has been most extensively studied in the context of ancestral and early developmental nutrition , 40, 41.