N = 34). This crosslinguistic transfer effect is well-documented in the scholarly literature for first language (L1) and second language (L2) learners  lower level of linguistic proficiency in the first language, as affected by acquiring a second, while children in the “additive” bilingual programs had the benefit of continued support of their first language. As Cummins .Cummins  develope Cummins  put it,In later work, Cummins  extendedinteraction between socio-cultural, linguistic and school program factors,” in which “the level of competence bilingual children achieve in their two languages acts as an intervening variable in mediating the effects of their bilingual learning experiences”  in the interpretation of the Threshold Hypothesis. Cummins seems to use the term “language proficiency” to refer to both competence and performance, including school literacy. MacSwan We suggest, then, that “transfer” of literacy across languages occurs because in the bilingual brain, both languages have access to the same cognitive resources. As Genesee et al.  observe It is apparent, then, that one does not see a relationship between “first language ability,” however that is to be conceived, and second language literacy, but between literacy in the first language and literacy in the second language; in other words, literacy is relatively independent of the particular language for which it was initially acquired. In this regard, the usual meaning of transfer, which implies that a process “moves” knowledge from one language to another, should be seen as strictly a metaphor: Rather than move, both languages have access to the same store of knowledge, available to learners regardless of how the knowledge was acquired in the first place, as Riches and Genesee  also sugThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dissemination bias occurs when only some results emerging from clinical research reach their intended audience in the knowledge translation process. Given that coverage decisions increasingly rely on evidence, it is important to explore the types of evidence considered. This paper aimed to examine the evidence base used by regulatory institutions involved in pricing and reimbursement of pharmaceuticals in a broad range of European countries, as well as their awareness of and approach towards dissemination bias.A mixed methods approach was adopted. Regulatory documents and published literature were identified in systematic searches and relevant documents were analysed. An online survey was carried out to verify and expand insights.Forty-two relevant regulatory documents and 10 publications were included. The survey had a 35% response rate, yielding valid responses for 13 countries. A fragmented impression was obtained for most countries indicating a general lack of transparency regarding both processes of decision-making and approaches towards unpublished information. Dissemination bias was rarely consistently considered. Practices for the identification and inclusion of all available evidence varied considerably, as did the influence of missing evidence on decision-making. Differences were often attributable to the regulatory context and/or institutional principles.Best practice is difficult to generalize given the identified variations. Individual exemplary practices support the necessity for institutional exchange at international level. Increased institutional commitment to transparency of methods and processes should be advocated.The online version of this article (doi:10.1186/s12961-016-0080-9) contains supplementary material, which is available to authorized users. Regulatory institutions responsible for determining the value of pharmaceuticals for coverage were thus encouraged to:In order for these recommendations to reach their full potential and be implemented in a meaningful manner, relevant institutions should also consider specific methodological issues emerging from this work given their remit and resources – adopt an approach that is as systematic as possible ; consider the consistent use of specific methods, such as funnel plots, to assess likelihood of bias in the evidence base; consult trial registries and perform consistency checks of submitted or identified evidence with study protocols and/or full study reports; and capture and publish potential conflicts of interest for those involved in the evaluation process.One of the main concerns of the authors during this project was the considerably limited amount of publicly available information for a number of countries on the procurement and utilization of evidence in general and, more specifically, their formal approach to unpublished data. From a methodological viewpoint, this is regrettable for a variety of reasons; existing exemplary practices may not have been identified while practices illustrated in this article may have been overestimated in the overall context of fragmented information. Furthermore, a distinct lack of information remains for a number of countries. Due to the nature of the survey, the low response rate (13/37 institutions) greatly impacted evidence completeness. Later research on other topics suggests that a shorter questionnaire administered by phone could have been more successful in this respect. The utilization of Google Translate comes with its own limitations as to the validity of information extraction. As data collection for this work was completed in 2012, any changes in institutional practices having come into effect in the meantime were not taken into consideration. Especially in light of newer changes at international level (e.g. EMA policy and WHO endorsement mentioned above), it would be interesting to revisit this issue in due time to map relevant progress.Despite the fact that the scientific community has been increasingly aware of dissemination bias and its consequences, our results showed that such concerns were sporadically embedded in coverage decision-making processes. There is a distinct lack of transparency regarding both the processes of evidence-based decision-making themselves and the consideration of unpublished data. While underlying differences make it difficult to extrapolate optimal approaches in an overarching way, steps, such as a requirement for manufacturers to submit all data and the encouragement of actions already taken by actors such as the EMA, can be crucial. Exemplary practices regarding the consideration of unpublished data and ensuring transparency were identified; in this respect, enhanced institutional collaboration could contribute to both awareness raising and knowledge exchange.


This article reviews contemporary approaches for bridging Ayurveda with evidence-based medicine. In doing so, the author presents a pragmatic assessment of quality, methodology and extent of scientific research in Ayurvedic medicine. The article discusses the meaning of evidence and indicates the need to adopt epistemologically sensitive methods and rigorous experimentation using modern science. The author critically analyzes the status of Ayurvedic medicine based on personal observations, peer interactions and published research. This review article concludes that traditional knowledge systems like Ayurveda and modern scientific evidence-based medicine should be integrated. The author advocates that Ayurvedic researchers should develop strategic collaborations with innovative initiatives like ‘Horizon 2020’ involving predictive, preventive and personalized medicine (PPPM). Ayu is life and Veda is science or knowledge. Charaka Samhita, Sushruta Samhita (~400 BC–200 AD) and Ashtanga Hridaya of Vagbhata are main classics, which give detailed descriptions of over 700 herbs and 6,000 formulations. Madhav Nidan (~800 AD), a diagnostic classic, provides over 5,000 signs and symptoms. Life in Ayurveda is conceived as the union of the body, senses, mind and spirit. The concept of Prakriti or individual nature has a central role in Ayurveda therapeutics. With over 400,000 registered Ayurveda practitioners, the government of India has a formal structure to regulate its quality, education and practice.Ayurveda is one of the traditional systems of medicine that practices holistic principles primarily focused on personalized health. Originated in India, Ayurveda is one of the ancient yet living health traditions. Ayurveda is commonly referred as ‘science of life’ because the Sanskrit meaning of Prolonged use of Ayurveda by people has also led to several home remedies for common ailments. Ayurvedic medicines contain sophisticated therapeutic formulations. Ayurveda is also a person-centered medicine (PCM), which deals with healthy lifestyle, health promotion and sustenance, disease prevention, diagnosis and treatment . The holPrakriti as well as seasons [Prakriti is being studied in context to biology and genomics [The need for scientific evaluation of Ayurveda has been recognized for a long time . Ayurved seasons . The scigenomics .Ayurveda as an ancient science of life has a long history, and its basic principles may be valid even today. However, essence of any science is a continuous quest for new knowledge through research, development and newer applications. The mode of manifestation of disease has changed. The geo-climatic environment, plants, animals and microbes have changed. Human behavior, lifestyle and genetics have changed. Clearly, classical Ayurveda of yesteryears cannot be blindly practiced without contemporary modifications. Continuous research on safety, quality and efficacy of Ayurvedic drugs and procedures is needed. Systematic documentation and critical analysis of clinical practice are necessary. Sanskrit savvy scholars from India should not be considered as the only custodians of knowledge and practice of Ayurveda. Several Western scholars like Meulenbeld have contributed to emergence of the new Ayurveda . Many coAyurveda was meant to be open for new ideas, principles and knowledge for continuous and systematic progress. However, its progression seems to be stalled during the last several centuries resulting in chronic stagnancy of today. Heritage pride and past glory-based emotional attitudes seem to be predominant among practitioners as against evidence-based quest of scientific research. There seem to be an evident complacency, defensive and dogmatic attitude and often pure sentimentalism rather than a pragmatic scientific outlook. We need to recognize that emotions, experience and evidence are not mutually exclusive. Becoming modern is not a crime; it does not prevent anyone from maintaining cultural identity. No tradition is a static entity; modernity results from evolving traditions. For instance, Charaka would not have ignored technologies like electron microscope if they had been available during his time . While aRecently, many experts and critiques have raised concerns that while the popularity of traditional and complementary medicine (T&CM) is growing, this sector is still grappling to discover appropriate models and demonstrate sufficient scientific evidence . AyurvedThe objective of any medical research should be to assess health effects, minimize bias, chance effects and confounders. A well-designed rigorous scientific research on medicines and therapeutic practices of Ayurveda is necessary. The Ayurveda sector has to take cognizance of important initiatives like standards for reporting observational epidemiology (STROBE) and consolidated standards on reporting trial (CONSORT) in the methodological domain to develop epistemologically sensitive appropriate methods. Evidence-based Ayurveda needs appropriate blends of modern science, rigorous trial methods and observational studies. Arguably, the nature of evidence in case of Ayurveda may be different from that of Western biomedicine. The status of Ayurveda as an evidence-based medicine is also reviewed here.In philosophy, evidence is closely tied to epistemology, which considers the nature of knowledge and how it is acquired. Many proponents of T&CM sector argue that inability to measure something using present scientific methods is not a proof of its nonexistence. However, inability of measuring something is certainly not a proof of its existence.It is also argued that future studies involving comparisons of T&CM systems with modern medicine need to be on the leveled playing field for evaluating outcomes from both an allopathic and a whole-system points of view . Insteadmahabhoota), three dynamic principles similar to humors (dosha), seven types of tissues (dhatus) and many other unique concepts. An introduction to basic concepts may be useful for readers who are not familiar with epistemology of Ayurveda [The epistemology of Ayurveda is based on the relation between microcosm and macrocosm involving five basic elements  based on Ayurveda knowledge has been shown to be useful in determination of individual Prakriti and personalized treatments [Ayurveda is uniquely patient-oriented where the Ayurvedic physician diagnoses, treats and dispenses medicine to every individual patient. This important principle can form the basis for a form of personalized medicine which will give maximum therapeutic efficacy and high safety to a particular person with a particular disorder, under specified conditions depending on individual constitution, and properties of materials. eatments .The conventional, experimental and diagnostic methods based on pathophysiology mostly rely on limited markers as evidence of health . ApplicaWorks of famous scientist Archie Cochrane on efficacy and effectiveness  and metaIn the following section, we have critically analyzed present situation regarding these two important aspects and have reviewed the status of Ayurveda as an evidence-based medicine.It is very important to review available evidence in the right perspective. In case of Ayurveda, the evidence can be drawn from two main sources. First, source of evidence may be based on historical, classical and present nature of clinical practice. Here, the documentation of practice to support various claims is very crucial. Mere reference to classical texts is not sufficient as evidence for practice. The second source of evidence may be based on scientific research to support various theories, medicines and procedures used in Ayurvedic medicine. A critical situation analysis of present status of clinical practice and scientific research on Ayurvedic medicine may be necessary at this stage.Arguably, the clinical practice of classical Ayurveda is rare. Ayurvedic practitioners are reported to adopt allopathic practices for better acceptance in urban settings . AlthougControlled clinical trials are taken as the highest level of evidence. Ayurveda lags far behind in scientific evidence in quantity and quality of randomized controlled clinical trials (RCTs) and systematic reviews. For instance, out of 7,864 systematic reviews in the Cochrane Library, Ayurveda has just one, while homeopathy and TCM have 5 and 14, respectively. Substantial grants have been allocated to ambitious national projects involving reputed laboratories. However, the design, methodology and quality of clinical trial on Ayurvedic medicines seem to lack the expected rigor . Of courFew noteworthy attempts related to research and practice include a national program on Ayurvedic biology , 39, AyuAs a result, Ayurvedic medicine continues to remain subcritical in research publications, which is an important indicator of external evidence . The prePrakriti, which broadly mean a body type or individual nature. An Ayurvedic physician determines the Prakriti of a patient so as to personalize treatment. The Ayurvedic description clearly suggests that the innate dispositions are represented by individual Prakriti, which represent phenotypes. Classifying humans based on phenotypes still remains a challenge to biomedical science. A number of research groups are now investigating the correlation between Ayurvedic phenotypes and individual human genotypes. A pioneering study showed significant correlation between HLA alleles and Ayurvedic Prakriti type [Prakritis may possess different drug metabolism rates associated with drug-metabolizing enzyme polymorphism. In another genotyping study, significant correlations between CYP2C19 genotypes and major classes of Prakriti types have been reported [Prakriti based on the principles of Ayurveda is underway. Now, it is hoped that going beyond genomics is necessary to understand how environment and behaviors can be responsible for inheritable changes when the genome remains unchanged. This science of epigenetics is seen as a future hope to get answers to many puzzles. It is felt that detailed understanding of Ayurvedic concepts like Prakriti may actually facilitate this process. However, no specific genotype has yet been specifically related to a Prakriti type.According to Ayurveda constructs, doshas are the dynamic principles, which govern a person’s physical, physiological and psychological functions including metabolism. Ayurveda describes three doshas namely vata, pitta, and kapha. The proportional domination of doshas in an individual is expressed as iti type . Later, reported . A projeshatkriyakaal elaborates a six-stage progressive transition from balanced to unbalanced stage leading to disease manifestation in a person. These six stages are unique and may help early recognition and early diagnosis much before onset of measurable clinical symptoms of diseases. It is possible to undertake a systematic cohort study by stratifying patients in the six categories. Each of the cohorts can be carefully followed up to study pathophysiological, genetic, and epigenetic and metabolomic differences. This may give leads towards the identification of new markers and early predictions, which can then be used for prevention and personalized treatments.Modern biomedicine recognizes progressive nature of diseases like cancer and diabetes. It is known that slow yet progressive pathophysiological changes result in a transition from a healthy state to diseased state. Ayurvedic concept of Thus, Ayurveda and PPPM concepts have many similarities, where both do not merely consider concept of disease in isolation but consider the diseased ‘person’. The need to define a common model of health and disease between the western and eastern knowledge systems has been pointed out earlier , 57. TheSeveral issues need to be addressed for Ayurveda to move towards acceptable evidence base. Concerns related to protocols, problems and potential of Ayurveda in context to evidence-based T&CM have been recently discussed . Few criA critical review and analysis indicate that the present Ayurvedic medicine is severely deficient in scientific evidence related to clinical practice and scientific research. Ayurveda sector needs to go beyond mere scholarly recitals, reviews and defensive interpretations, which are abundant in current literature. Ayurveda needs to be studied and experimented with help of new models based on modern science and biology. Ayurvedic medicine needs more rigorous scientific research for evaluating safety, quality and efficacy . Many leThis review and analysis is carried out with a caveat that the methods and evidence approach of biomedicine may not be directly applicable to Ayurveda. However, either Ayurveda has to discover its own methodology and approach for evidence or should face the critical analysis as per the conventional approach of EBM. Avoiding any critical appraisal under the pretext that it is a holistic system and that the present methods like randomized controlled trials are not applicable may not sustain for a long time.The Ayurvedic sector should urgently recognize and address the need for scientific evidence . SystemaThe new philosophy of health care is moving from illness to wellness, from treatment to prevention and early diagnostics and from generalized approach to personalized medicine. As discussed in this review, there are several similarities between the concepts of PPPM and Ayurveda. Search of novel models for integrative medicine indicates the need for collaborations between traditional systems like Ayurveda and contemporary western biomedicine . Agreeab


There is increasing recognition of gaps between best scientific evidence and clinical practice. This systematic review aimed to assess the volume and scope of peer-reviewed cancer research output in the years 2000, 2005, and 2010.Eligible papers were published in English and reported on evidence-practice gaps in cancer care. The electronic database Medline was searched for three time periods using MeSH headings and keywords. Abstracts were assessed against eligibility criteria by one reviewer and checked by a second. Papers meeting eligibility criteria were coded as data-based or non-data-based, and by cancer type of focus. All data-based papers were then further classified as descriptive studies documenting the extent of, or barriers to addressing, the evidence-practice gap; or intervention studies examining the effectiveness of strategies to reduce the evidence-practice gap.A total of 176 eligible papers were identified. The number of publications significantly increased over time, from 25 in 2000 to 100 in 2010 (p < 0.001). Of the 176 identified papers, 160 were data-based. The majority of these (n = 150) reported descriptive studies. Only 10 studies examined the effectiveness of interventions designed to reduce discrepancies between evidence and clinical practice. Of these, only one was a randomized controlled trial. Of all data-based studies, almost one-third (n = 48) examined breast cancer care.While the number of publications investigating evidence-practice gaps in cancer care increased over a ten-year period, most studies continued to describe gaps between best evidence and clinical practice, rather than rigorously testing interventions to reduce the gap. Evidence-based practice is the ‘conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’ . There iThe past decade has been marked by increases in both cancer incidence and survival ,14. HoweGiven increased acknowledgement of the need to address evidence-practice gaps in cancer care, it might be expected that research efforts to ensure effective translation of knowledge into clinical practice would also have increased over this time period. Although not without limitations , examiniWhile volume of research output provides an indication of the amount of work being conducted in a particular field, it fails to provide information about the type or quality of work. The effective translation of evidence into practice is complex and depends on a number of factors, one of which is the type of research evidence generated . To advaet al. [In 2010, Evensen et al.  examinedet al. . Providiet al. . Translaet al.  argues tTo examine in the cancer literature in the years 2000, 2005 and 2010:1. The number of publications examining evidence-practice gaps;2. The number of data-based versus non-data-based publications examining evidence-practice gaps, including the number describing evidence practice gaps compared to the number evaluating interventions to reduce evidence practice gaps;3. The number of data-based publications examining evidence-practice gaps by cancer type and research design.Eligible papers were those published in English in 2000, 2005, and 2010 that reported on evidence-practice gaps in cancer care. The year 2000 was selected as the starting point for this review given that the influential report by the National Cancer Board was published in 1999 . StudiesThe electronic database Medline was searched using the OVID platform. The search strategy included three categories of search terms: guideline adherence/evidence based practice, cancer, and treatment types  and rejected if the reviewer determined from the title and abstract that the study did not meet inclusion criteria. Full text copies of the remaining publications were retrieved and further assessed against eligibility criteria to confirm or refute inclusion. Papers meeting the eligibility criteria were then categorized as follows:1. Data-based or non-data-based: Data-based publications were those reporting new data or new analysis of existing data. Non-data-based publications included review, commentary, discussion, or summary papers.2. Cancer type: All data-based papers were classified according to the cancer type of the study sample according to the International Classification of Diseases for Oncology  and body3. Research design: All data-based papers were further classified into one of the following categories: Descriptive studies using cross-sectional study designs to document or describe the evidence-practice gap or barriers to addressing the evidence-practice gap; Intervention studies using experimental designs to test strategies to reduce the evidence practice gap. Studies using an experimental design were also assessed as to whether the design was one of the four types allowed by the EPOC criteria- randomized controlled trials, clinical controlled trials, controlled before and after studies, or interrupted time series studies.A random sample of 10% of papers identified as eligible was checked for relevance and double-coded by a second reviewer (MC).Chi-Square tests for equal proportions were conducted to determine whether the total volume of research output changed over time, and whether the number of descriptive studies changed over time.A total of 4,507 citations were retrieved using the key words. After assessment against the eligibility criteria and double coding by a second reviewer (with 100% agreement achieved), 176 relevant studies meeting the eligibility criteria were included in the review  used cross-sectional designs to describe evidence-practice gaps Figure . Only teReducing the gap between best evidence and clinical practice in cancer care will improve patient morbidity and mortality -8 and reWhile descriptive research provides important information about current practice, it does not maximize research benefits by comparing the effectiveness of approaches to improve care. The small number of intervention studies, and in particular the small number that used rigorous evaluation designs, may be explained by the difficulty of carrying out well-controlled intervention trials in this field. Changes to clinical practice may require changes to processes of care, clinician knowledge, and organizational culture, so the unit of analysis for such studies is often the hospital, ward, or clinic. These types of system-focused interventions are often incompatible with randomized controlled designs where the unit of randomization is the individual . An alteThe small number of intervention trials may also be the result of a perception in clinical oncology that optimal cancer care is already being delivered to patients and, therefore, research to ensure translation of clinical research into practice is not needed. It is simplistic to presume, however, that new evidence is routinely integrated into clinical practice guidelines, policy, and then clinical care ,32. ChanThe finding that a large proportion of research effort has been directed toward breast cancer care is in accordance with previous findings that breast cancer research dominates the quality of life research field . ProstatThese results should be considered in light of several limitations. First, grey literature such as reports, policy documents, and dissertations were not included, nor were protocol papers. While this information may be relevant, grey literature is not peer-reviewed and therefore may not meet the high standards of quality associated with peer-reviewed publication. Inclusion of grey literature may also have biased the review given that papers related to work known by the authors and their network would have been more likely to have been identified than other works. Second, only one author screened the retrieved citations/abstracts. While a random 10% of included studies were double coded by a second reviewer with perfect agreement, this is a limitation of the search execution. Third, there are limitations to using volume of research output as a measure of research effort ,38. Due Reducing discrepancies between best evidence and clinical practice is an area of ongoing need across all fields of healthcare. A prerequisite for the effective transfer of evidence into practice is methodologically rigorous research that identifies where evidence-practice gaps exist, and develops and tests interventions to close the gap. The small number of intervention studies addressing evidence-practice gaps in cancer care highlights a clear need to shift research efforts from descriptive studies to robust experimental studies if patients are to receive optimal care. The relatively high number of studies on the translation of evidence into practice in breast cancer care suggests that greater research effort should be directed towards other cancers with high incidence and disease burden such as lung cancer.The authors declare that they have no competing interests.JB and RSF conceived of and designed the review. JB, AB, KJ, and MC undertook data extraction. All authors contributed to drafting of the manuscript and have read and approved the final manuscript.Search Strategy.Click here for fileReview Protocol.Click here for fileList of citations for included studies.Click here for file


Background: Soil-transmitted helminths (STH) have acute and chronic manifestations, and can result in lifetime morbidity. Disease burden is difficult to quantify, yet quantitative evidence is required to justify large-scale deworming programmes. A recent Cochrane systematic review, which influences Global Burden of Disease (GBD) estimates for STH, has again called into question the evidence for deworming benefit on morbidity due to STH. In this narrative review, we investigate in detail what the shortfalls in evidence are. Methodology/Principal Findings: We systematically reviewed recent literature that used direct measures to investigate morbidity from STH and we critically appraised systematic reviews, particularly the most recent Cochrane systematic review investigating deworming impact on morbidity. We included six systematic reviews and meta-analyses, 36 literature reviews, 44 experimental or observational studies, and five case series. We highlight where evidence is insufficient and where research needs to be directed to strengthen morbidity evidence, ideally to prove benefits of deworming. Conclusions/Significance: Overall, the Cochrane systematic review and recent studies indicate major shortfalls in evidence for direct morbidity. However, it is questionable whether the systematic review methodology should be applied to STH due to heterogeneity of the prevalence of different species in each setting. Urgent investment in studies powered to detect direct morbidity effects due to STH is required. Soil-transmitted helminth (STH) infections are among the most prevalent of the neglected tropical diseases (NTDs), characterised by chronic and subtle impacts on human health and development. They rarely cause direct mortality; instead they are major contributors to morbidity. Morbidity effects of STH infection are difficult to quantify given the long duration of infection, often over many years, presence of other concurrent diseases, and factors such as poverty and malnutrition, to which they are strongly linked, and which can confound measures of STH-associated morbidity. Accurate quantification of STH-associated morbidity and disease burden is critical to rationalise large-scale deworming programmes.Debate exists around the health benefits and cost-effectiveness of STH intervention strategies, rising to prominence with Cochrane systematic reviews reporting equivocal evidence of health benefits –4 and a Global burden of disease (GBD) studies quantifying STH burden, with the most recent estimates published in 2012 , have alIt is timely to revisit the pool of knowledge for STH impact on health, with a particular focus on how recent evidence contributes to knowledge gaps, and to critically appraise the approaches being used in systematic reviews, particularly the Cochrane systematic review, to disentangle why results are consistently inconclusive.In this narrative review, we critically appraise narrative and systematic reviews and consider the recent observational and experimental literature, covering both STH morbidity and treatment associations with health outcomes. We explore the reasons for the reported lack of effect in the most recent Cochrane systematic review and investigate why conclusions regarding STH impact on haemoglobin do not concur with other systematic reviews ,13. ThisAscaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum. The nematode Strongyloides stercoralis was not included in this review. Specifically, the following combination of text and Medical Subject Headings (MeSH) terms was used:  and . The search was limited by English language. This search aimed to (1) identify narrative and systematic reviews of STH morbidity and (2) identify recent research papers on STH-associated morbidity. Article abstracts were reviewed and literature was retrieved if there was specific reference to a morbidity or mortality outcome from STH or if they could not be excluded . Reference lists of identified articles were cross-checked. We further cross-checked peer-reviewed literature with information from United Nations, World Health Organization (WHO), and several other non-government organisation websites.We searched scientific literature in the MEDLINE database (January 2000 to January 2016) for evidence of any morbidity or mortality outcomes associated with Once identified, narrative and systematic reviews were analysed to determine current knowledge and evidence gaps Tables  and 2. CWe further investigated recent evidence to determine whether knowledge gaps identified in earlier reviews were being addressed. Informed by the evidence summaries Tables  and 2, w(i)If studies related to hookworm impact on haemoglobin or anaemia, we included only experimental evidence since the 2010 systematic review was done;(ii)If studies related to impact on haemoglobin or anaemia of other STH, or any STH impact on physical  or cognitive measures of morbidity, we included studies from 2006 (the date of the last major STH review) and considered all observational and experimental evidence, with the exception of case series and case reports; and(iii)A. lumbricoides or T. trichiura acute complications, we included five case series, but not individual case reports.In the absence of any identified epidemiological investigations into We looked at coinfections among STH species. For STH and non-STH parasite interactions, STH and vaccine interactions, and associations with allergies, atopy, and asthma, we note that effects on morbidity are likely to be synergistic and that research is under way to investigate these effects. However, discussion of these is beyond the scope of the current review.A. lumbricoides and T. trichiura). For this reason, studies that reported prevalence or intensity of infection only (indirect morbidity measures), or changes in these following interventions, were not reported. Furthermore, this means that for some studies, not all study outcomes were included in our evidence tables. Critical appraisal checklists were again followed to assess these studies [After applying the above search criteria, studies were further excluded from  studies .Tables No recent epidemiological studies addressing STH entry and establishment in the human host were identified. Sequelae  associatThe evidence for negative impact of STH infections is strongest for morbidity due to blood loss and anaemia. There is clear evidence that hookworms in particular cause blood loss from feeding on mucosal tissue in the small intestine , therebyEvidence from systematic reviews and recent experimental studies is mixed; not all studies have found an impact of hookworm  on either haemoglobin levels or anaemia. Three systematic reviews , confirm previous observational direct correlations between intensity of hookworm infection and reduced haemoglobin, or improvements in haemoglobin levels following deworming ,13,53. TIt is only since 2002 that deworming has been advocated during pregnancy (after the first trimester), with the result that experimental data on maternal and child outcomes are relatively recent and more evidence is needed. Whilst data are somewhat dated, iron-deficiency anaemia has been suggested to be responsible for 20% of maternal deaths worldwide , with esT. trichiura in blood loss and anaemia. T. trichiura-associated blood loss has been previously inferred to only become significant in heavy infections [T. trichiura and A. lumbricoides (but low hookworm) endemic environment, moderate to heavy A. lumbricoides infection was a risk factor for anaemia in school-aged children [Studies vary with regards the involvement of fections ; newer efections  is in agchildren . FurtherT. trichiura, A. lumbricoides, and/or hookworm on height but not weight, weight but not height, both height and weight, height and head circumference, and some studies found no impacts at all . This has been epidemiologically linked to recurrent biliary invasion by A. lumbricoides in endemic areas [Severe clinical complications such as trichuris dysentery syndrome (TDS), or intestinal obstruction and hepatopancreatitis as a result of e burden , althouge burden . In the e burden . It is aic areas . Similaric areas . There aAncylostoma ceylanicum, which recent data show to be the second most prevalent hookworm species after N. americanus, in some Asian countries [A. ceylanicum may have more severe morbidity than A. duodenale [A. ceylanicum-associated morbidity are somewhat dated and highlight the evidence gap arising from a failure to investigate morbidity associations. Diagnosis of A. ceylanicum requires coprodiagnostic molecular biology techniques not readily available in developing countries; however, in the current era of large-scale deworming programmes, there is growing impetus for utilisation of contemporary diagnostic methods, hence renewed focus on this hookworm species is needed.Current STH prevalence and burden estimates do not include ountries . Whilst uodenale ,113. StuIt is clear that many morbidities associated with STH cannot be investigated in an experimental design and, further, that many associations  are not feasible to investigate at all. In assessing evidence for deworming on STH-associated morbidities, the Cochrane Collaboration has exclusively considered RCT and quasi-RCT evidence in its systematic reviews of deworming. As has been raised elsewhere ,8, this Cochrane systematic reviews are regarded as the benchmark for high-quality evidence, utilising rigorous methodologies undertaken in accordance with a set protocol. In the most recent Cochrane review  on the hUnder the rules of the Cochrane Collaboration, the systematic review protocol must be produced prior to undertaking the review . It is cA. lumbricoides, in blood loss, to indicate that pooling of STH is not an accurate way of assessing morbidity. Similarly, it is also not accurate to pool different anthelmintic treatments of known and well reported [With the analysis of unscreened children, trials have been pooled irrespective of STH species, treatment types, and drug distribution strategies. Conceptually, pooling trials in systematic reviews is appropriate; however, for STH there is a very high level of heterogeneity, and this approach is prone to methodological flaws. By considering RCTs conducted in different locations in which screening has not been done, there is no baseline assessment of STH prevalence and/or intensity. The underlying assumption is that baseline prevalence is the same between intervention and control groups, which enables post-intervention assessment attributable to the intervention . Whilst justifiable for RCTs, this causes a difficulty for systematic review methods, as there is marked STH heterogeneity in different endemic areas and, if baseline testing is not done, there must be another estimate to determine the STH of greatest prevalence in the population  to ensure that heterogeneity is addressed when pooling RCTs. In the systematic review, no baseline of STH prevalences are reported. Whilst evidence is limited, there is sufficient prior knowledge of differential impacts of STH on morbidity outcomes, e.g., the role of hookworms, but not reported ,116 veryreported , is currreported , or diffreported . Such poThe rationale for pooling studies may have been data-driven or aimed at replicating the deworming programme context. A more robust approach would be to apply the method of Smith and Brooker , who useThe lack of evidence is correctly and clearly pointed out by the Cochrane authors with regards treatment of children with known STH infection. Participant and trial numbers for many outcomes were very low and many of the results were not sufficient to meta-analyse. Lack of sufficient data was also the reason why subgroup analysis by age was not conducted. This is, however, an extremely important evidence gap given differing age prevalence profiles of STH and the likely greater morbidity in preschool-aged children . The authors conclude that most evidence is of very low, low, or moderate quality. The most useful and important conclusion of the systematic review is that there is a major shortfall in evidence for most morbidities to feed into meta-analyses in the first place. Until such time as evidence is generated, meta-analyses will not be able to appropriately assess the health benefits of STH interventions.If the protocol was publicly available, we could specifically ascertain whether the included trials met the protocol, whether excluded trials did not meet the protocol, and whether other trials should have been identified under the terms of the published search strategy. Other authors have noted omission of RCTs that ideally should have been considered . FurtherIn this manuscript, we have found that there is a paucity of recently collected data to inform our knowledge of STH morbidity. In particular, relatively little quantifiable evidence of STH morbidity has been forthcoming in recent years. Of the evidence that has been provided, few firm conclusions can be drawn. Perhaps this, too, is a reflection of the insidiousness of STH. Alternatively, this could be partly a result of trials that are powered to measure different primary outcomes; secondary morbidity outcomes may therefore be inadequately powered for effects to be detectable. Furthermore, this may be because intervention trials are impossible to conduct over sufficient time periods to assess deworming impacts on morbidity in the manner that such programmes are delivered in real-world settings . There is also a possibility that our review has applied selection criteria that could have excluded key evidence. We considered that applying these criteria was the most accurate way to differentiate between direct and indirect STH morbidity measures. The main discrepancy that the Cochrane systematic review highlights is insufficient and heterogeneous underlying evidence. This is reinforced by our own findings.We do have an evidence problem regarding STH morbidity and health effects of deworming. The use of prevalence and, to a lesser extent, intensity of infection as indicators for intervention planning, monitoring, and evaluation may have reduced the impetus to investigate more direct morbidity measures. As a consequence, we might not currently be able to prove the benefits of deworming. Furthermore, evidence of morbidity may become increasingly hard to detect over time if prevalence and intensity continue to reduce in populations. This is obviously a good outcome, but a poor basis upon which to make any assessments. Our main conclusion is that further investments in appropriately designed studies that are powered to measure changes in direct STH morbidity indicators are urgently required.There is a paucity of quantifiable evidence of STH morbidity in recent years when assessed by direct morbidity measures such as changes in height, weight, haemoglobin, and cognition.The most recent Cochrane systematic review has assessed possible benefits of deworming on morbidity outcomes by pooling RCTs of deworming regardless of individual infection status, STH species, type of anthelmintic drug, and distribution strategy. In our opinion, this is methodologically inaccurate given current knowledge of STH heterogeneity. There may be insufficient evidence to prove benefits of deworming, but this is not the same as the authors’ conclusion of lack of an effect.Careful consideration needs to be given to use of systematic reviews of RCTs for measuring improvements in morbidity from deworming. Furthermore, there needs to be clarification of the role of observational evidence for assessing STH-associated morbidity given that not all morbidity investigations are feasible within an RCT design.Studies designed to detect direct morbidity from STH are urgently required to strengthen evidence for deworming.1Taylor-Robinson DC, Maayan N, Soares-Weiser K, Donegan S, Garner P. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Cochrane Database Syst Rev. 2015;7: CD000371.2Smith JL, Brooker S. Impact of hookworm infection and deworming on anaemia in non-pregnant populations: a systematic review. Trop Med Int Health. 2010;15(7): 776–95.3Gulani A, Nagpal J, Osmond C, Sachdev HP. Effect of administration of intestinal anthelmintic drugs on haemoglobin: systematic review of randomised controlled trials. BMJ. 2007;334(7603): 1095.4Brooker S, Hotez PJ, Bundy DA. Hookworm-related anaemia among pregnant women: a systematic review. PLoS Negl Trop Dis. 2008;2(9): e291.5Haider BA, Humayun Q, Bhutta ZA. Effect of administration of antihelminthics for soil transmitted helminths during pregnancy. Cochrane Database Syst Rev. 2009(2): CD005547


L. bulgaricus, N-acetylmuramidase (mur), was cloned and sequenced (GenBank accession number: KF157911). Mur gene overexpression and gene knockout vectors were constructed based on pMG76e and pUC19 vectors. Recombinant plasmids were transformed into L. bulgaricus ljj-6 by electroporation, then three engineered strains with pMG76e-mur vector and fifteen engineered strains with pUC19-mur::EryBII were screened. The autolysis of the mur knockout strain was significantly lower and autolysis of the mur overexpressed strain was significantly higher compared with that of the wild type strain ljj-6. This result suggested that the mur gene played an important role in autolysis of L. bulgaricus. On the other hand, autolytic activity in a low degree was still observed in the mur knockout strain, which implied that other enzymes but autolysin encoded by mur were also involved in autolysis of L. bulgaricus.Autolysis of lactic acid bacteria (LAB) plays a vital role in dairy processing. During cheese making, autolysis of LAB affects cheese flavor development through release of intracellular enzymes and restricts the proliferation of cells in yogurt fermentation and probiotics production. In order to explore the mechanism of autolysis, the gene for the autolytic enzymes of  Lactic acid bacteria are used as starter cultures for dairy fermentation and therefore their lysis is of special interest. In cheese making, ripening is an extremely important process since it defines the flavor and texture of the cheese, which differentiates the many varieties. The process is very slow, generally between three weeks and two (or more) years. This makes cheese making an expensive business. Several technological methods have been used to accelerate ripening, such as increasing the ripening temperature, the use of modified starter cultures, and the addition of exogenous enzymes Generally, autolysis is mainly caused by lactic acid bacteria autolysins which are defined as endogenous enzymes that hydrolyze covalent bonds in the peptidoglycan of the cell wall. Five types of enzymes with lytic activity against peptidoglycan have been described for Gram-positive bacteria L. bulgaricus Ljj-6, exploring the relationship between N-acetylmuramidase gene and L. bulgaricus autolysis, and laying the foundation for the directional control of lactic acid bacteria autolysis in future studies.The aim of the present study was to clone and sequence the N-acetylmuramidase gene from the bulgaricus were routinely grown at 37°C in Man-Rogosa-Sharpe (MRS) medium  under static conditions. MRS was autoclaved for 15 min at 121°C. The strain morphology was observed by light microscopic Olympus CX41.The parental strains and plasmids that were used in this study are listed in E. coli and L. bulgaricus cells by use of BIOMIGA Plasmid Miniprep kits (PD1211-01). Chromosomal DNA was isolated from L. bulgaricus cells by use of BIOMIGA Bacteriall gDNA kits (GD2411-01).Routine molecular biology techniques were performed according to standard procedures. Restriction and modifying enzymes (New England Biolabs) were used as recommended by the manufacturer. Plasmid DNA was prepared from L. bulgaricus ljj-6 using the sodium dodecyl sulfate/proteinase K/cetyltrimethylammonium bromide (CTAB) method mur gene was amplified from the DNA template by PCR with ExTaq DNA polymerase (Takara) and primers containing an salI site and an sphI site  with a program consisting of 1 cycle at 95°C for 4 min, then 35 cycles of 95°C for 1 min, 55°C for 1 min, and 72°C for 2 min, and finally 1 cycle of 72°C for 8 min. Products were quantified by comparing the intensity of the product DNA band to that of a 2000 bp marker standard in 1% agarose. Each DNA fragment was ligated into the pGEM-T Easy vector (Promega) according to the manufacturer’s instructions at 16°C overnight. The recombinant plasmid was then transformed into Escherichia coli DH5α competent cells. Positive clones of transformed cells were selected and sequenced at Shanghai Invitrogen Company, China.DNA was extracted from mur gene was subcloned into pMD18-T in E. coli DH5α to generate the recombinant plasmids pMD18T-mur. Plasmid pMD18T-mur and pMG76e were extracted from E. coli DH5α, respectively. The recombinant plasmid pMD18T-mur and the vector pMG76e were digested with salI and sphI, and purified with the QIAprep Spin Miniprep kit. Ligase was used to construct the recombinant of pMG76e-mur  according to the manufacturer’s instructions. The electroporated mixture was immediately diluted with 1 mL of MRS broth and incubated for 2 h at 36°C and then plated on solid MRS media containing erythromycin (200 ug/mL) and incubated for 48 h at 36°C.650) was adjusted to about 1 to control the number of cells in the bacterial suspension to about 1×107 cells/mL. Then 1 mL bacteria liquid was centrifuged at 4°C  after which the supernatant was discarded. The cells were resuspended in 1 mL PI-PBS solution (20 mmol/L). Cell suspensions were dyed by PI-PBS in a dark environment for 30 min at 4°C. A 630 nm long pass filter was used to collect the red fluorescence (FL3488 nm) and 1×105 cells were collected from each sample. Test time ranged from 40 to 100 s, depending on the concentrations of the cell suspensions. Data were analyzed by CellQuest online analysis system. FCM enumerations were accurate to 104 cells/mL. The rate of autolysis was defined as the ratio of the positive cell number with PI dying to the total cell number. Comparisons between groups were tested by One - Way ANOVA analysis and LSD test.Detection of cell autolysis rate was done using the PI-FCM method: the cultured cells in liquid were collected after centrifugation , followed by washing two times with PBS buffer and then resuspended. The bacterial suspension absorption value .The PCR amplification was performed with the genome DNA plate from obtained , which wTCC11842 . Howevermur gene approximately 650 bp in size was amplified. SalI and SphI restriction sites were introduced to the mur gene to facilitate its insertion into the multiple cloning site of pMG76e. The recombinant plasmid was amplified and isolated from E. coli DH5α transformants and digested with SalI and SphI. Analysis of the digestion mixtures by 1.0% agarose gel electrophoresis revealed that the cells contained both the 4.2 kb pMG76e-mur fragment and the 654 kb mur fragment, indicating that the mur gene had been successfully incorporated into pMG76e, in addition PCR reaction . Colonies of positive transformants were visible after 48 h of incubation at 37°C. Three engineered strains (L. bulgaricusO1-O3) with pMG76e-mur vector and fifteen candidate engineered strains (L. bulgaricus k1-k15) with pUC19-mur::EryBII were screened. The fifteen candidate colonies (k1-k15) were then transferred onto MRS agar plate containing ampicillin (50 µg/ml). Possible double-crossover mutants had lost their capability to grow in the presence of ampicillin but were still resistant to erythromycin. Finally six double-crossover mutants  were chosen by the second round screening.The recombinant plasmids pMG76e-mur and pUC19-mur::EryBII were transformed into The genome DNA was extracted from the the mur knockout strain k12 which has been cultured in MRS broth for 24 hours. The PCR amplification for the mutant genome DNA and wildtype genome DNA was performed using the Primer 3 and 4 . The resmur reconstituted strain, pMG76e-mur was introduced into the mur deletion mutant k12 by electroporation. The mur-reconstituted strain was designated rk12. The autolysis of rk12 was detected and the result . After the initial breakdown of milk caseins by the lactococcal cell envelope proteinase , autolysis of starters causing release of these enzymes usually has beneficial consequences Autolysis of lactic acid bacteria in media and buffer systems has previously been studied by Sugahara et al. mur sequences is difficult to explain the huge variation in the extent of autolysis found in different L. bulgaricus strains. In addition, the completed Lactobacillus bulgaricus ATCC11842 genome sequence shows the presence of several open reading frames that putatively encode cell wall hydrolases having up to 47% predicted amino acid identity to mur gene. These enzymes may have roles in the autolysis of L. bulgaricus. Further studies are needed to clarify the number and types of autolytic enzymes within different strains and species of L. bulgaricus and also how they work.Differences in


While I was a PhD reciprocal exchange student at University of California, Los Angeles(UCLA), in 2011, I had the pleasure to meet great names in international Orthodontics. Iwas introduced to Dr. Greg Huang, a brilliant professor and an extraordinary human being..In addition to having a brilliant clinical and academic career, Dr. Huang is also chair ofone of the most renowned Orthodontics programs worldwide: at the University ofWashington.Undoubtedly, thanks to Dr. Huang, Orthodontics has followed scientific evidence-basedguidelines, therefore leaving a number of merely clinical assumptions behind. Once ourhonored guest has been duly introduced, I express my sincere gratitude to my colleaguesSteven Lindauer, Luciane Menezes, Weber Ursi and Marcos Janson for accepting my invitationto participate actively in this interview. I am also thankful for having been given thehonor by Dental Press to conduct such an experience. I wish readers have a readingexperience as pleasing and valuable as the scientific path that brought us here.Durante o meu doutorado sanduíche na Universidade da Califórnia em Los Angeles (UCLA), em2011, tive a satisfação de entrar em contato com grandes nomes da Ortodontia internacional.Entre esses, foi-me apresentado, pelo Dr. Carlos Jorge Vogel, um brilhante professor e umapessoa extraordinária, o Dr. Greg Huang. Por trás de uma brilhante carreira clínica eacadêmica, o Dr. Huang é, atualmente, chefe de um dos programas de Ortodontia maisrespeitados do mundo, na Universidade de Washington. Com certeza, graças ao Dr. Huang, aOrtodontia vem buscando diretrizes baseadas em evidências científicas e, assim, deixandopara trás muitos "achismos" clínicos. Feitas as devidas apresentações do nosso ilustreentrevistado, dedico meus cordeais agradecimentos aos colegas Steven Lindauer, LucianeMenezes, Weber Ursi e Marcos Janson, por aceitarem o convite para participar ativamentedessa entrevista. Agradeço, ainda, a Dental Press, pela honra, a mim concedida, de conduziressa experiência. Desejo a todos os leitores que essa leitura seja tão prazerosa e ricaquanto o trajeto científico que nos trouxe a essa entrevista.André Wilson MachadoI went to Dental School at the University of Florida ('87), and then to the Universityof Washington for my Master of Science in Dentistry and Certificate in Orthodontics(both in '89). I was in private practice in Florida for 10 years. During that time, Itaught one day each month at the University of Florida. In 1999, I returned to theUniversity of Washington as an Acting Assistant Professor. I also enrolled in the Masterof Public Health program, and completed my MPH in Epidemiology, in 2001. I became anAssociate Professor in 2005, and then a Full Professor in 2011. In 2008, I was selectedas Chair of our Department.What is the approach that you and your faculty take in educating new orthodontists atthe University of Washington? In other words, what is the university teachingphilosophy? Steven Lindauer, Andre W. MachadoI believe our education could be described as evidence-based, open-minded,outcomes-focused, and patient-centered. We have tried to steer clear of orthodontic"dogma", and we place a high emphasis on reading the literature critically. Clinically,we have many affiliate faculties, all of whom are encouraged to teach graduate studentstheir own particular philosophy and techniques. We feel that exposure to many facets ofOrthodontics best prepares our students for real world practice.When I initially decided to focus on an academic career, my intention was primarily toteach clinically. I never thought that my training in Epidemiology would lead to acareer that has become increasingly involved with clinical research. In the past, weprimarily conducted retrospective, single-center studies at the University ofWashington. Now, of course, prospective studies carried out at multiple sites or inresearch networks are gaining traction. I have been extremely fortunate to conductclinical studies in a regional practice-based research network that operated from2005-2012, and now, in a national practice-based network.I also never imagined that I would have the opportunity to collaborate with so manytalented colleagues from all over the world. In my various roles with the University ofWashington, the American Association of Orthodontists (AAO), orthodontic journals, andseveral textbooks, I have had the opportunity to be exposed to many interesting facetsof our profession. As defined by the American Dental Association (ADA), an evidence-based approach is basedon three important elements: a clinician's education and experience; the scientificliterature; and a patient's values, preferences, and unique condition. All three ofthese must be considered in arriving at treatment that is most appropriate for anindividual.I became interested in evidence-based practice due to my training in Epidemiology. Manyprinciples of evidence-based Medicine were developed by two physician/epidemiologists. As you know, our literatureis full of studies that report opposing findings, leaving us confused and wondering whatto believe. Evidence-based Dentistry provides a framework from which to objectivelyevaluate our literature, and in my opinion, knowing how to employ evidence-based methodsis an invaluable skill that all practitioners should master. Fortunately, the guidelinesto perform systematic reviews and meta-analyses have continued to evolve and improve,and reviewers are also doing a better job identifying well-conducted reviews forpublication. Thus, the systematic reviews and meta-analyses that are being publishedcurrently are usually of high quality. Our textbook, Evidence-based Orthodontics, was a very enjoyable project for SteveRichmond, Kate Vig, and me. We were fortunate to have many talented orthodontists fromaround the world contribute by assembling information on evidence-based methods, as wellas by summarizing the evidence on many important orthodontic topics. We are lookingforward to working on a second edition in the near future.-The recent evidence on self-ligating brackets seems to indicate that they reduce chairtime, but probably do not decrease alignment time or treatment time significantly.Because so many patients have Class II malocclusions due to mandibular retrognathia, itmakes sense that orthodontists would like to enhance mandibular growth with functionalappliances. While this appears to happen to some degree when assessing immediately aftertreatment, very little additional growth seems to be maintained long term.,,I do not consider myself an expert in the field of TMD, but except for some uniqueindividuals or in some extreme malocclusions, TMD seems to be minimally affected bymalocclusion.,We conducted a practice-based study on third molar removal in the USA.Relapse in adult patients can occur quickly, and retention should be part of thetreatment planning process. In general, tooth movement is more difficult in adults, and,therefore, more robust methods must be considered for the retention phase. For example,I am more likely to use bonded retainers in adults with significant irregularity.Similarly, bonded retainers may be indicated to assist with holding extraction spacesclosed. From our post-retention sample at the University of Washington, we have foundthat irregularity increases with each decade of life, so our practice of long-termretention seems well justified. Perhaps in the future we will have some biologicalagents or new techniques to stabilize teeth in their corrected positions. The literature on open bite treatment is voluminous, but the literature on open bitestability is significantly less. What we seem to know is that surgical treatment mayhave a little higher rate of long-term stability than orthodontic treatment.Based on the most recent Cochrane review, fluoride varnish applied every 6 weeks mayreduce the occurrence of white spot lesions 70%.In my career as an orthodontic educator, perhaps the most rewarding aspect is playing arole in the education and development of our young orthodontists. It is always excitingto welcome a new class of students, and to see their progression in skills and knowledgeduring the time they are at the University of Washington. I would suggest to them three things. First, take full advantage of the learningopportunities that are afforded to you during your training. Unless you pursue anacademic career, most of you will never be in such a rich, intense, and diverseeducational environment. Learn from your faculty and your peers, try as many techniquesas possible, and keep an open mind to new ideas. Assess your results honestly. Second, educate yourself in the science of our profession. Learn about evidence-basedmethods, keep up with the literature, and attend meetings. Employ an evidence-basedapproach to your daily practice by using the best evidence to guide your clinicalrecommendations. Third, always place your patient's best interests first. Recommend the same treatmentsto them that you would recommend to your own family members.


Underserved women are at high risk for smoking relapse after childbirth due to their unique socioeconomic and postpartum stressors and barriers. Mobile text messaging technology allows delivery of relapse prevention programs targeted to their personal needs over time.To describe the development of a social-cognitive theory-based and evidence-guided text messaging intervention for preventing postpartum smoking relapse among inner city women.Guided by the cognitive-social health information processing framework, user-centered design, and health communication best practices, the intervention was developed through a systematic process that included needs assessment, followed by an iterative cycling through message drafting, health literacy evaluation and rewriting, review by target community members and a scientific advisory panel, and message revision, concluding with usability testing.All message content was theory-grounded, derived by needs assessment analysis and evidence-based materials, reviewed and revised by the target population, health literacy experts, and scientific advisors. The final program, “Txt2Commit,” was developed as a fully automated system, designed to deliver 3 proactive messages per day for a 1-month postpartum smoking relapse intervention, with crave and lapse user-initiated message functions available when needed.The developmental process suggests that the application of theory and best practices in the design of text messaging smoking cessation interventions is not only feasible but necessary for ensuring that the interventions are evidence based and user-centered. Tobacco use has remained the single most important modifiable cause of adverse pregnancy outcomes in the United States. Smoking accounts for 30% of deliveries of infants with low birth weights, 8% of preterm births, and 5% of all perinatal deaths -3. SmokiAlthough there are programs designed to motivate underserved women who are at increased risk for smoking relapse ,13, undeA key barrier that emerges for the delivery of evidence-based postpartum programs is access to the new mother.Encouragingly, due to the availability of modern technologies, one particularly well suited but under-utilized technology involves the use of mobile telephones to deliver health-related information to these hard-to-reach populations. Currently 90% of Americans own and use a mobile telephone with text messaging service and 47% of Americans use mobile phones to gain access to information on a daily basis . BecauseOne successful example of using a text messaging program for pregnant women is the “Text4baby” program, which sends targeted health messages to promote healthy pregnancies and healthy babies . FurtherWith use of a user-centered approach, the intervention development followed a series of iterative steps to ensure that all content was understandable and evidence-based. Guided by the C-SHIP framework and health communication best practices, the text messaging intervention was developed through a systematic process that included needs assessment interviews, followed by an iterative cycling through text message drafting, revision through health literacy evaluation, review by target community interviews via cognitive response interviews, scientific advisory panel evaluation and feedback, and message revision, followed in turn by usability testing of the entire program.The order of the development processes was established from our research team’s multimedia intervention development experience ,48 and tConstructs from the C-SHIP model were used to guide the intervention development strategy and content. The C-SHIP model offers a unifying theoretical framework for assessing and addressing the psychosocial relapse factors typically experienced by postpartum women -52. The Participants (N=30) were recruited via flyers and staff referrals at 3 Women, Infants, and Children (WIC) clinics located in the inner city Philadelphia region. Interested women were invited to participate if they: (1) were 18 years of age or older, (2) had quit smoking for at least 1 pregnancy, and (3) had given birth to at least 1 child in the past 3 years. Interviews lasted approximately 20 minutes and included specific questions addressing the experiences, motivators, and techniques that had helped women maintain smoking abstinence after pregnancy, as well as personal, social, and environmental factors that triggered a postpartum relapse. Their mobile phone and text message use and preferences were also obtained. Upon completion of the interview, participants received a $20 gift card as compensation for their time and input.Following an initial review of the interview transcripts, the research team developed a coding scheme based on the C-SHIP model. Responses categorized under C-SHIP were coded into 1 of the 5 psychosocial relapse risk factors. Subcategories in each domain were established as relevant themes emerged from the data. The intention behind coding responses into the C-SHIP processes was to systematically assess the major psychosocial relapse risk factors and identify the unique pattern of challenges faced by low-income, inner city women during the postpartum period.This information was used to guide the development of the Txt2commit intervention text message content.As reported above, text message content development was grounded in the C-SHIP theoretical model and guided by a formative research approach through a needs assessment interview phase with the target population. In addition, we conducted a comprehensive literature review, as well as an evidence-based guideline search for the potential adoption of existing materials to adapt to the target population. Content component constructs included factors such as messages for increasing awareness of the risks associated with smoking on infant’s health (knowledge), techniques for controlling exposure to stressful cues that trigger the urge to lapse/relapse (affective distress), reinforcing beliefs about the woman’s ability to sustain smoking absence (self-efficacy), considering the consequences of continued smoking , and identifying new behaviors to be substituted for smoking-related activities (self-regulatory skills). To respond effectively to situations in which the participant required an instant message to deal with craving or lapse situations, text messages were developed to offer strategies and emotional support to cope with craving/lapse situations and strategies for how to get back on track.To ensure that the messages were designed for a low health-literate audience, 2 health literacy experts systematically evaluated all drafted messages using software and their health literacy expertise. The program Health Literacy Advisor  was used to scan and highlight the text for complex terms, complex health terms, polysyllabic words , and long sentences .The findings from the health literacy analysis were then evaluated by the 2 health literacy experts and the research team to further revise the text messages to improve readability.Following the revisions for health literacy, the messages were reviewed and vetted by participants (N=30) recruited at the 3 WIC offices with the same eligibility criteria identical to those of the needs assessment phase.Each participant reviewed 21 messages and was asked to think aloud about the messages, paraphrase the content, and respond to other inquiries and probes using the cognitive response technique . SpecifiA multidisciplinary scientific advisory panel was convened to provide further insight into the cultural sensitivity, appropriateness, and message appeal of the intervention for the target population. The panel (N=7) was composed of smoking cessation professionals, with expertise in psychosocial behavior, health communication, WIC management, and community perspectives. Panel members were provided with a list of messages , and the C-SHIP coding guide for each message. Members of the advisory panel evaluated the appropriateness of the content of each of the messages and provided their recommended revisions to the wording and readability of each message from their individual perspective and expertise. The research team then reviewed the advisors’ comments and made necessary modifications to produce the final program.Ten participants, with the same eligibility criteria identical to those of the needs assessment phase, were recruited to pretest the program for usability testing following the scientific advisory review phase. The program was delivered over 1 week. Participants were provided with phones equipped with text messaging service and were instructed as follows: complete (open and confirm receipt of) 7 system-initiated messages (1 per day), and initiate 3 crave (described below) and 3 lapse message requests (described below) during the 1-week testing phase. Participants were debriefed individually by research staff at the conclusion of the usability testing and received a $20 gift card as compensation for their time and input. They were asked to provide the following overall feedback: system-initiated text message understandability, cultural appropriateness of text message wording, ease of use of crave and lapse functions, and problems encountered in use of the program. Each participant was also asked to provide additional comments concerning the intrusiveness, timing, and general burden imposed by using the program. Feedback was compiled and evaluated by the research team to determine whether adjustments in the messages, system, or study procedures warranted correction or adjustment, with subsequent implementation of necessary corrections and adjustments.The findings of the needs assessment interviews are reported elsewhere; participant characteristic information is presented in With regard to phone habits, most participants  had a home phone, but even more were mobile phone users . In addition, 93% (28/30) of participants reported that they used their mobile phones for texting, and 83% (25/30) reported that they texted on a daily basis. However, none of the participants in this population owned a smartphone. Therefore, our intervention only used text-messaging delivery, which is compatible with all models of mobile phones. Furthermore, when inquiring about their attitudes toward text message styles for a smoking cessation/relapse program, a more formal tone of content without the use of common text messaging abbreviations was preferred because it was thought to increase the creditability of the program. Information gathered from the needs assessment interviews was synthesized by the research team to guide the drafting of the text message content.A pool of 204 messages was initially developed based on the findings of the needs assessment and a review of the relevant literature.The emerging themes from the needs assessment content analysis were also integrated into the message drafting. The C-SHIP model provided a theoretical guide for message creation because this model indicates specific areas that are especially relevant for health interventions. Smoking facts from several evidence-based resources, including the National Cancer Institute’s fact sheet concerning the harms of smoking, were identified and extracted to be included within the messages where appropriate.The text messaging intervention developed included 3 main components: low-frequency messages to be sent during the third trimester (1 per week for engagement before the start of the main intervention), high-frequency messages to be sent after participants had given birth (1 message per day for 1 month), and messages available upon participant request when experiencing a craving for a cigarette or a lapse into having smoked one. The messages were systematically and comprehensively developed to address each component, so that some messages were specific to the prenatal or postpartum period and some to the situation of craving or lapsing. The drafted messages were coded across the 5 C-SHIP constructs by the research team.The initial assessment of the 204 text messages identified a number of issues, including the use of polysyllabic words, complex health terms, complex nonmedical terms, and long sentences. After the 2 health literacy experts reviewed and modified each message in collaboration with the research team, a second assessment using Health Literacy Advisor revealed a significant reduction in the following health literacy problems: a 72% reduction in polysyllabic words, 79% reduction in complex health terms, 91% reduction in complex nonmedical terms, and 47% reduction in long sentences. Most of the complex terms remaining in the text messages were words that pertained to the message content and the study, such as tobacco, smoking, and cancer. During the message review interview phase described below, these words were specifically tested and found to be readily recognized by study participants, indicating that they were not difficult to read or understand.Messages were reviewed by 30 women at 3 different WIC clinic sites using the cognitive response interview technique. All messages were evaluated by the advisory panel in relation to the relevance of the messages to the population, as well as their coverage of factors involved in the C-SHIP framework. A final review of the advisory panel input by the research team resulted in slight modifications to 50% of the messages and 21 additional messages being eliminated.Ten participants were recruited from the same 3 WIC clinic sites as in the interview phases to participate in a 1-week usability testing session. Each participant was provided with a mobile phone and instructions for mobile phone and message use. Each participant received 7 system-initiated messages over a 1-week period and was instructed to initiate 3 crave and 3 lapse message requests. Among the 10 enrolled participants, 8 successfully completed the testing and responded to the evaluation interview. All 8 participants identified the messages as helpful and reported being satisfied with the messages, as well as with the crave and lapse functions. They all stated that they would use the program and recommend it to others. They also suggested changes, including making the system-initiated messages more frequent (3 per day) and adding voice and video messages to the program. Based on participants’ feedback, the research team finalized the “Txt2commit” program, which provided: (1) 1 text message per week during the prenatal period (27 weeks gestation and on) to enhance and sustain program engagement, (2) 3 text messages daily during the first postpartum month, and (3) crave and lapse functions so that participants could request additional messages when feeling the need. The final program was tested in a larger feasibility pilot study, results of which will be reported elsewhere for ease of communication. The development of the Txt2commit mobile text messaging intervention relied on a combination of theory and evidence, systematic attention to health literacy issues, and integration of a user-centered approach throughout the developmental process. This research adds to the emerging literature supporting the critical role of a comprehensive strategy for the design of mHealth interventions and highlights the value of a scientifically based health literacy focus. This study aimed to stimulate discussion among target users about how to use mobile text messaging as a platform for delivering smoking cessation interventions for underserved postpartum women, as well as demonstrate a rigorous process of development to ensure that the messages are potent, easily understood, and delivered in an effective manner. Using an iterative developmental process, a multidisciplinary team, and user input, the text messaging intervention was progressively developed and refined based on formative participatory evaluations to achieve a culturally—and linguistically—appropriate psychosocial program that provides relevant content to underserved women who quit smoking during their pregnancies.The needs assessment, message review, and cognitive response interviews were all essential to identify gaps in women’s needs in postpartum and smoking relapse trigger stressors, which resulted in relevant and appropriate text messaging content and format. Furthermore, the health literacy review and painstaking editing significantly increased the readability and accessibility of the information. The final usability testing confirmed the preferred frequency of message delivery and the usefulness of the crave and lapse functions, prior to the final production and pilot study implementation. The intensity and functionalities of our final intervention program design is comparable to most of the studies in the text messaging smoking cessation literature, with an average of 1-5 text messages per day and the availabilities of crave and lapse functions ,58,59.As technology advances become more common as a delivery mechanism for health behavior interventions, it is important to recognize that the impact will depend on the interdigitation of well-designed content, technology, and end user input.Given advances in the field of behavior medicine, it has become increasingly clear that knowledge alone does not change behavior. Likewise, technology alone does not change behavior, but the combination of theory-based best practice approaches in content development, coupled with technology, increases access and reach and has great promise for improving outcomes through attention to evidence-based cessation barriers. The strengths of the study include the use of an established C-SHIP theoretical framework, application of health communication and health literacy best practices to guide text messaging content drafting and revision, extensive input from a community-based sample at various steps in development, and the use of a multidisciplinary expert advisory board. This approach extends our prior research, where the C-SHIP framework was successfully applied to smoking cessation and multimedia intervention behavior change studies ,52,60,61This study provides insight into the systematic development of text messaging interventions for use in other behavior change contexts. The prevalence of mobile phone use and text messaging among the present underserved sample indicates the potential of text messaging as a delivery modality in a variety of health settings and behaviors. Therefore, the development concepts used in this intervention should be applicable to the development process for other health-related mHealth interventions, especially those targeted to diverse underserved populations. One important lesson learned was that although text messaging was an acceptable channel to communicate smoking relapse messages, postpartum women indicated their preference that these messages be written using formal language to highlight the credibility of the information.As the vision of eHealth/mHealth is beginning to be actualized, development must also allow for the involvement of “consumers with diverse perspectives, circumstances, capacities, and experiences in the design of, evidence-based eHealth tools” . This st


Purpose. The management of diabetic neuropathy (DN) can be challenging. There exist many guidelines for DN management, but the quality of these guidelines has not been systematically evaluated or compared. The objective of our study was to assess the quality of these guidelines as a step toward their future optimization, the development of international guidelines, and, ultimately, the improvement of the care process. Methods. Relevant data were selected to identify international guidelines. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool was used to evaluate the quality of the selected guidelines. In addition, the reviewers summarized and compared all of the recommendations from the included guidelines for DN's management. Results. Thirteen guidelines were included after the selection process. According to AGREE II, few guidelines scored well for all three aspects of DN management. Detailed comparisons revealed that these guidelines provide inconsistent recommendations, making it difficult for diabetes clinicians to choose appropriate guideline. Conclusions. The quality of most guidelines for the management of DN should be improved. Further studies should concentrate on developing internationally accepted and evidence-based guidelines that could be used for clinical decision making to improve patient care. Diabetic neuropathy (DN) is a neuropathic disorder characterized by diabetes mellitus (DM) with peripheral neuropathy lacking other possible causes. DN, one of the most common long-term complications of DM, affects nearly 50% of patients with diabetes , 2. DN iClinical practice guidelines (CPGs) are developed systematically to help practitioners and patients choose the appropriate care for specific clinical situations. Indeed, it has been demonstrated that the proper use of high-quality guidelines can improve patient outcome , 7; thusTo the best of our knowledge, no published appraisals of the quality of contemporary guidelines for the treatment of DN are available online. The purpose of this study was to systematically retrieve all existing guidelines regarding the treatment of DN and to assess and compare their quality using Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and to compare the recommendations given by different guidelines, with the goal of helping diabetes clinicians working in busy clinical practices choose the most appropriate guidelines and recommendations.A systematic search was performed to retrieve relevant guidelines regarding the management of DN. Guidelines were identified using computer searches of the Guidelines International Network Library, the National Institute for Health and Clinical Excellence (NICE) database, the Medline database, and the National Guidelines Clearinghouse. Additional guidelines were obtained by reviewing the homepages of international medical institutions and other relevant websites. The searches were conducted using the following controlled terms: diabetic neuropathy, diabetic peripheral neuropathy, and painful neuropathy. Additionally, we used terms corresponding to the following internationally agreed-upon classifications : (1) forWe developed a series of inclusion criteria to select guidelines: (1) the target group included patients with DN; (2) the guidelines focused on the management of DN; (3) the full text was available online; (4) the guidelines were written in English; and (5) the guidelines were published between June 1, 2004, and June, 2014.Guidelines were excluded according to the following criteria: (1) did not meet the definition of a guideline or satisfy the definition of a narrative review; (2) focused on the treatment of DM but did not address DN in detail; or (3) offered a review of DN but did not present specific recommendations. Furthermore, if different versions of the guidelines were available, only the latest edition was selected.The successful treatment of DN must include three key elements: (1) the implementation of strategies to minimize risk factors and complications, (2) management based on the pathogenetic mechanisms of DN, and (3) the use of therapies to relieve symptoms , 13. Thehttp://www.agreetrust.org/). Ultimately, one reviewer summed all of the scores of the individual items to calculate each domain score using the following formula: (obtained score − minimum possible score/maximum possible score − minimum possible score) × 100%.We evaluated the selected guidelines with respect to the three independent aspects of DN treatment utilizing Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument (2013 version). The AGREE II tool is a validated assessment instrument that is designed to provide a framework for the evaluation and monitoring of clinical guidelines , and it After the above steps, we provided an overall assessment of each set of guidelines. A guideline was “strongly recommended for use in practice” if most domains (4 or more) scored above 60%. A guideline was “recommended for use with some modification” if most domains scored between 30% and 60%. “Not recommended for use in practice” implied that most of the domains of the guideline were scored as approximately or below 30%.A total of 102 guidelines were collected during the primary literature selection process, though many were excluded after applying the inclusion and exclusion criteria. Because specific guidelines for focal and multifocal DN are lacking, we merely evaluated the guidelines for generalized symmetric polyneuropathies. Ultimately, 13 guidelines , 15–25 wThe recommendations in these guidelines can be divided into three parameters: avoidance of risk factors and complications, treatment based on the pathogenetic mechanisms of DN, and symptom management. The differences and similarities between the guidelines will be discussed for each of these parameters.The first parameter analyzed was the avoidance of risk factors and complications. The recommendations in this domain were consistent to some extent. Nine guidelines reached unanimous agreement on stable and optimal glycemic control. Providing comprehensive foot care was suggested by eight guidelines. Intensive multifactorial interventions targeting blood pressure, glucose and lipid levels, and other lifestyle factors were considered by five guidelines, whereas six guidelines proposed that patients make lifestyle modifications. Moreover, seven guidelines concurred that patients should receive psychological support .The second parameter focused on treatment based on the pathogenetic mechanisms of DN. The antioxidant alpha-lipoic acid was recommended for pathogenetic treatment by two guidelines, and the guidelines provided by the Statement by American Diabetes Association (SADA) and the Working Group on the Diabetic Foot from the French-Speaking Society of Diabetology (SFD) advised implementing angiotensin-converting enzyme inhibitors to improve microcirculation in neuropathy patients. Nevertheless, the remaining eight guidelines failed to provide any recommendations on this topic .α2-δ ligands, and serotonin noradrenaline reuptake inhibitor drugs for pain relief. Moreover, several guidelines advised patients to utilize certain nonpharmacological interventions. In addition, some guidelines offered explicit first- to fourth-line therapies and drug combinations , with an average score of 61.9% . HoweverCPGs are now ubiquitous in almost every aspect of clinical practice and health policy, and it is commonly believed that the proper use of high-quality guidelines can improve patient outcomes. In the modern era, health care practitioners may easily obtain guidelines from web-based guideline databases. To the best of our knowledge, our study is the first comprehensive and detailed evaluation of the quality of international evidence-based guidelines according to three independent aspects of DN treatment. This paper offers an overview of the quality and content of various international guidelines for the management of DN. We evaluated 13 guidelines using AGREE II tool and found that the overall quality of most of the guidelines was relatively moderate, with the exception of the SIGN, NICE, and PNICE guidelines. In general, some key recommendations provided by the included guidelines were discrepant, making it a bit difficult for diabetes clinicians working in busy clinical practices to choose the appropriate course of action.Our study revealed that most guidelines had identical recommendations concerning this aspect. However, AGREE II  scores iOnly four guidelines , and American Academy of Neurology (AAN)) made any recommendations regarding this aspect. In fact, over the past two decades, many mechanism-based translational medicine investigations and clinical trials have focused on the pathogenetic management of DN. To our surprise, numerous guidelines appeared to fail to mention this aspect, which may indicate that these guidelines may not use systematic methods to search for evidence. Although four guidelines provided explicit recommendations, they unfortunately did not receive high scores using AGREE II tool  , suggestMost guidelines received good scores on this aspect . We noteRegarding the first- to fourth-line drugs, there were discrepancies across most of the guidelines, likely due to the ambiguity of the grading standard. There were rare normative or clear standards for the definition of a first- or second-line drug worldwide, and the specific boundary between first- and second-line drugs is unclear. It is clear that the definitions of first- and second-line therapy should be standardized in further studies.In regard to combination therapy, it is well known that combination therapy is commonly prescribed for neuropathic pain. Combination therapy may also be a helpful option as a stepwise approach if the initially used drugs insufficiently decrease pain. Combination therapy may also result in greater tolerability . HoweverCranial neuropathy, truncal neuropathy, focal limb neuropathy, proximal motor neuropathy, and chronic inflammatory demyelinating polyneuropathy are not uncommon and are important aspects of DN, which has a serious impact on the quality of life of patients with diabetes . HoweverIn conclusion, the results of this study indicate that despite the general acceptance of the approach and quality criteria related to the development of evidence-based guidelines, different guidelines may produce conflicting conclusions and differing recommendations for similar clinical situations. Some discrepancies are valid and reasonable, but others may not. Therefore, the quality of most guidelines for the treatment of DN should be improved. Clinical practice guidelines should be developed according to AGREE II criteria to support good clinical practice and effective patient care. High-quality trials and meta-analyses should be used during the guideline development process, and different societies and countries should collaborate in guideline development to generate consensus recommendations for clinical practice. Further studies should concentrate on establishing internationally accepted and evidence-based guidelines that could be used for clinical decision making regarding the treatment of DN to enhance patient care and to improve patient outcomes.