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Nuno Montenegro - One of the best experts on this subject based on the ideXlab platform.
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guidelines for the management of spontaneous preterm labor identification of spontaneous preterm labor diagnosis of preterm premature rupture of membranes and preventive tools for preterm birth
2011Co-Authors: Gian Carlo Di Renzo, Lluis Cabero I Roura, Fabio Facchinetti, Aris Antsaklis, Gregor H Breborowicz, Eduard Gratacos, P Husslein, Ronnie Lamont, Anton V Mikhailov, Nuno MontenegroAbstract:Dear Editor, With great interest I read the recently published guidelines for the management of spontaneous preterm labor [1]. I was delighted to see that unlike the previous guidelines published in 2006 [2], these new ones also take into consideration the diagnostic marker insulin-like growth factor binding protein-1 (IGFBP-1) that I have worked with since the early 80s. However, I would like to bring the readers’ attention to some errors and points that may be misleading regarding evaluation of IGFBP-1 as a marker of ruptured fetal membranes (ROM) and in comparing it with placental α microglobulin-1 (PAMG-1). Firstly, human IGFBP-1 is a well characterized protein since more than 20 years [3,4]. Its synthesis by the liver and decidua, and levels in amniotic fluid and other body fluids have been thoroughly examined in all stages of pregnancy [5,6] and the data have been published in peer-reviewed journals. Meanwhile, the data available on PAMG-1 is more limited and partly confusing. In the most often cited papers regarding the PAMG-1 levels in amniotic fluid, blood and other body fluids [7–9], the values are quite different from those reported in the guidelines. This makes comparison between IGFBP-1 and PAMG-1 difficult. IGFBP-1 has been used as a marker of ROM since the mid 90s (Actim PROM test). Since then, several studies have consistently shown that this test identifies membrane rupture with high accuracy. Unfortunately, many of these studies were omitted in the analysis presented in Table I of the guidelines comparing the performance of the different tests [10–12]. As a consequence, the sensitivity and specificity of the IGFBP-1 test remain underestimated. For example, the lowest sensitivity (74%) is from a study by Lockwood 1994 using a quantitative radioimmunoassay with frozen samples in the laboratory with a different detection limit and assay conditions from the current IGFBP-1 based bed-side PROM test [13]. Secondly, the guidelines state that the detection limit of PAMG-1 with Amnisure ROM test (5 ng/ml) is lower than the detection limit of IGFBP-1 with Actim PROM test (25 ng/ml). This comparison is irrelevant, since the quoted levels of PAMG-1 protein in amniotic fluid (2000−25,000 ng/ml) are clearly lower than the known levels of IGFBP-1 (10,500−350,000 ng/ml [14]), which naturally calls for a need of a lower detection limit. In the guidelines the lowest level of IGFBP-1 is quoted to be 27 ng/ml in early pregnancy. Such low levels have not been reported at pregnancy weeks clinically relevant for diagnosis of ROM [15]. Thirdly, the sensitivity and specificity of any test has to be interpreted in the clinical context. The methods used for estimation of the accuracy and reliability of the PAMG-1 test compared to the IGFBP-1 test are questionable for several reasons. For example, samples of pure blood-free amniotic fluid obtained during intra-operative amniocentesis at cesarean section were diluted with 0.9% saline and serial dilutions were tested using both tests [16,17]. The study design does not correspond to the bed-side situation where amniotic fluid is contaminated by vaginal discharge or other possible fluids like urine, semen or blood that may affect the test result causing false positives, if the test is too sensitive. A high rate of positive PAMG-1 test results has been found among patients with intact membranes and labor at term [18] and in patients with a short cervix [19]. This data has not been considered when analyzing the specificity of PAMG-1 test. Also, the publication on the intra-amniotic dye test and its comparison with the PAMG-1 test is a congress abstract only, with no information on the numbers of patients or the study design [20]. Finally, IGFBP-1 test results have repeatedly been shown to be unaffected by the presence of blood [10,21,22]. Indeed, the monoclonal antibody used in the Actim PROM test does not recognize the highly phosphorylated IGFBP-1 which is the predominant isoform in maternal and fetal blood and decidua [4]. Since blood may be present in approximately 25% of cases with suspected PROM, this information is critical in order to estimate the accuracy and clinical usefulness of the marker. Suspected rupture of membranes in the presence of bleeding is the most challenging situation in the clinic, since the therapeutic measures differ depending on whether the membranes in such a case are intact or not. Yet, no information is available on the accuracy of the PAMG-1 test in patients with suspected membrane rupture and bleeding since patients with bleeding have systematically been excluded in PAMG-1 clinical studies, suggesting that PAMG-1 test cannot be used in such challenging cases. The statement that presence of blood up to 50% does not interfere with the PAMG-1 test result is only based on a Conference Poster, reporting serial dilutions of peripheral blood in 0.9% saline in vitro [23]. Again, the study design is not equivalent to the clinical situation where amniotic fluid in cervicovaginal swab sample is mixed with vaginal secretion and other possible contaminants. Also, this high rate of positive Amnisure results in the presence of blood raises a question on the validity of the reported range in the maternal blood (0.5–2 ng/ml) that should not react in a test with a detection limit of 5 ng/ml. Considering all the points above, the currently available data does not unequivocally support the superiority of the PAMG-1 test as compared with the IGFBP-1 test.
Florence Kurttila - One of the best experts on this subject based on the ideXlab platform.
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effective stakeholder engagement design and implementation of a clinical trial swog s1415cd to improve cancer care
2019Co-Authors: Sarah Barger, Sean D Sullivan, Ari Bellbrown, Brad Bott, Anne Marie Ciccarella, John Golenski, Mark Gorman, Judy Johnson, Karma L Kreizenbeck, Florence KurttilaAbstract:The Fred Hutchinson Cancer Research Center has engaged an External Stakeholder Advisory Group (ESAG) in the planning and implementation of the TrACER Study (S1415CD), a five-year pragmatic clinical trial assessing the effectiveness of a guideline-based colony stimulating factor standing order intervention. The trial is being conducted by SWOG through the National Cancer Institute Community Oncology Research Program in 45 clinics. The ESAG includes ten patient partners, two payers, two pharmacists, two guideline experts, four providers and one medical ethicist. This manuscript describes the ESAG’s role and impact on the trial. During early trial development, the research team assembled the ESAG to inform plans for each phase of the trial. ESAG members provide feedback and engage in problem solving to improve trial implementation. Each year, members participate in one in-person meeting, web Conferences and targeted email discussion. Additionally, they complete a survey that assesses their satisfaction with communication and collaboration. The research team collected and reviewed stakeholder input from 2014 to 2018 for impact on the trial. The ESAG has informed trial design, implementation and dissemination planning. The group advised the trial’s endpoints, regimen list and development of cohort and usual care arms. Based on ESAG input, the research team enhanced patient surveys and added pharmacy-related questions to the component application to assess order entry systems. ESAG patient partners collaborated with the research team to develop a patient brochure and study summary for clinic staff. In addition to identifying recruitment strategies and patient-oriented platforms for publicly sharing results, ESAG members participated as co-authors on this manuscript and a Conference Poster presentation highlighting stakeholder influence on the trial. The annual satisfaction survey results suggest that ESAG members were satisfied with the methods, frequency and target areas of their engagement in the trial during project years 1–3. Diverse stakeholder engagement has been essential in optimizing the design, implementation and planned dissemination of the TrACER Study. The lessons described in the manuscript may assist others to effectively partner with stakeholders on clinical research.
Norman Waugh - One of the best experts on this subject based on the ideXlab platform.
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clinical and cost effectiveness of donepezil rivastigmine and galantamine for alzheimer s disease a rapid and systematic review
2001Co-Authors: Andrew Clegg, Jackie Bryant, T Nicholson, Linda Mcintyre, S De Broe, Karen Gerard, Norman WaughAbstract:Background Alzheimer’s disease is the most common cause of dementia and is characterised by an insidious onset and slow deterioration. The estimated prevalence of Alzheimer’s disease for a standard health authority (500,000 people) is about 3330. Current service involves a wide range of agencies, and drug therapy for some patients. Objectives To provide a rapid and systematic review of the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine in the symptomatic treatment of people suffering from Alzheimer’s disease. Methods A systematic review of the literature was undertaken. Data sources Searches were made of electronic databases, including MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effectiveness, NHS Economic Evaluation Database, National Research Register, Science Citation Index, BIOSIS, EconLit, MRC Trials database, Early Warning System, Current Controlled Trials, TOXLINE, Index of Scientific and Technical Proceedings, and Getting Easier Access to Reviews. All sources were searched over the period covered by the databases up to March/July 2000. Biblioýraphies of related papers were assessed for relevant studies and experts were contacted for advice and peer review, and to identify additional published and unpublished references. Manufacturer submissions to the National Institute for Clinical Excellence (NICE) were reviewed. Study selection Studies were included if they fulfilled the following criteria. Intervention: donepezil, rivastigmine or galantamine used to treat Alzheimer’s disease. Participants: people diagnosed with Alzheimer’s disease who meet the criteria for treatment with donepezil, rivastigmine and galantamine. Outcomes: measures assessing changes in cognition, function, behaviour and mood, quality of life (including studies assessing carer well-being and carer-input), and time to institutionalisation. Design: systematic reviews of randomised controlled trials (RCTs) and RCTs comparing donepezil, rivastigmine or galantamine with placebo or each other or non-drug comparators were included in the review of effectiveness. Economic studies of donepezil, rivastigmine or galantamine used to treat Alzheimer’s disease that included a comparator (or placebo) and both the costs and consequence (outcomes) of treatment were included in the review of cost-effectiveness. Studies in non-English language, and abstracts and Conference Poster presentations of systematic reviews, RCTs and economic evaluations were excluded. Two reviewers identified studies by independently screening study titles and abstracts, and then by examining the full text of selected studies to decide inclusion. Data extraction and quality assessment Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer, with any disagreements resolved through discussion. The quality of RCTs was assessed using the Jadad scale and the quality of systematic reviews was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. The quality of economic evaluation studies was assessed by their internal validity (i.e. the methods used) using a standard checklist, and external validity (i.e. the generalisability of the economic study to the population of interest) using a series of relevant questions. Data synthesis The clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine were synthesised through a narrative review with full tabulation of results of all included studies. In the economic evaluation, the reviewers assessed whether adjustments could be made to existing models to reflect the current situation in England and Wales. Results Clinical effectiveness Donepezil – three systematic reviews and five RCTs (plus four studies from industry*) were found. Results suggest that donepezil is beneficial when assessed using global and cognitive outcome measures. Rivastigmine – three systematic reviews and five RCTs (plus two studies from industry*) were found. Results suggest that rivastigmine is beneficial in terms of global outcome measures. Galantamine – one systematic review and three RCTs (plus three studies from industry*) were found. Results suggest that galantamine is beneficial in terms of global, cognitive and functional scales. Summary of benefits It is difficult to quantify benefits from the evidence available in the literature. Statistically significant improvements in tests such as ADAS-cog (Alzheimer’s Disease Assessment Scale cognitive subscale) may not be reflected in changes in daily life. Costs/cost-effectiveness Nine economic studies were found, which could not be closely compared. Donepezil – the five studies of donepezil produced a variety of cost-effectiveness estimates. While the base cases showed increased effectiveness and were cost saving in two studies, they were more costly in the other three. When sensitivity analyses are taken into consideration, estimates fluctuated more widely and there were, in some cases, conflicting results for sub-group analyses, thus casting doubt on the robustness of the estimates. Rivastigmine – of the four rivastigmine studies, the oldest has been surpassed by more recent evaluations. Cost-effectiveness ratios in two studies could not be extracted as the associated overall effectiveness was not reported and interpretation of the costs results alone is difficult due to the exclusion of drug therapy costs. The fourth study found average net costs within the first year, but a cost saving at 2 years, but it was not clear whether the data presented could be translated into incremental cost-effectiveness ratios. Galantamine – no published economic evaluations of galantamine were found. For each drug there was a further economic analysis performed by industry*. Economic implications of prescribing these drugs are uncertain. The main issue is not drug costs per se, but the impact across different sectors. Currently, this remains unclear since the financing and provision of care for patients with Alzheimer’s disease in England and Wales is complex and difficult to unravel. Any cost savings would depend mainly on release of funds from residential care. * Unpublished data, submitted as commercial in confidence Conclusions Implications On the basis of the current evidence, the implications of the use of donepezil, rivastigmine or galantamine to treat patients with Alzheimer’s disease are unclear. The main issue is whether the modest benefits seen in the outcome measures used in the trials would translate into benefits significant to patients. Future research Future research should include: development of quality-of-life instruments for patients and their carers; comparisons of benefits from drugs with those from other interventions; identification of those patients likely to benefit from drug treatment; development of protocols of treatment withdrawal if not beneficial; economic evaluations. Ongoing research should provide valuable evidence.
Gian Carlo Di Renzo - One of the best experts on this subject based on the ideXlab platform.
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guidelines for the management of spontaneous preterm labor identification of spontaneous preterm labor diagnosis of preterm premature rupture of membranes and preventive tools for preterm birth
2011Co-Authors: Gian Carlo Di Renzo, Lluis Cabero I Roura, Fabio Facchinetti, Aris Antsaklis, Gregor H Breborowicz, Eduard Gratacos, P Husslein, Ronnie Lamont, Anton V Mikhailov, Nuno MontenegroAbstract:Dear Editor, With great interest I read the recently published guidelines for the management of spontaneous preterm labor [1]. I was delighted to see that unlike the previous guidelines published in 2006 [2], these new ones also take into consideration the diagnostic marker insulin-like growth factor binding protein-1 (IGFBP-1) that I have worked with since the early 80s. However, I would like to bring the readers’ attention to some errors and points that may be misleading regarding evaluation of IGFBP-1 as a marker of ruptured fetal membranes (ROM) and in comparing it with placental α microglobulin-1 (PAMG-1). Firstly, human IGFBP-1 is a well characterized protein since more than 20 years [3,4]. Its synthesis by the liver and decidua, and levels in amniotic fluid and other body fluids have been thoroughly examined in all stages of pregnancy [5,6] and the data have been published in peer-reviewed journals. Meanwhile, the data available on PAMG-1 is more limited and partly confusing. In the most often cited papers regarding the PAMG-1 levels in amniotic fluid, blood and other body fluids [7–9], the values are quite different from those reported in the guidelines. This makes comparison between IGFBP-1 and PAMG-1 difficult. IGFBP-1 has been used as a marker of ROM since the mid 90s (Actim PROM test). Since then, several studies have consistently shown that this test identifies membrane rupture with high accuracy. Unfortunately, many of these studies were omitted in the analysis presented in Table I of the guidelines comparing the performance of the different tests [10–12]. As a consequence, the sensitivity and specificity of the IGFBP-1 test remain underestimated. For example, the lowest sensitivity (74%) is from a study by Lockwood 1994 using a quantitative radioimmunoassay with frozen samples in the laboratory with a different detection limit and assay conditions from the current IGFBP-1 based bed-side PROM test [13]. Secondly, the guidelines state that the detection limit of PAMG-1 with Amnisure ROM test (5 ng/ml) is lower than the detection limit of IGFBP-1 with Actim PROM test (25 ng/ml). This comparison is irrelevant, since the quoted levels of PAMG-1 protein in amniotic fluid (2000−25,000 ng/ml) are clearly lower than the known levels of IGFBP-1 (10,500−350,000 ng/ml [14]), which naturally calls for a need of a lower detection limit. In the guidelines the lowest level of IGFBP-1 is quoted to be 27 ng/ml in early pregnancy. Such low levels have not been reported at pregnancy weeks clinically relevant for diagnosis of ROM [15]. Thirdly, the sensitivity and specificity of any test has to be interpreted in the clinical context. The methods used for estimation of the accuracy and reliability of the PAMG-1 test compared to the IGFBP-1 test are questionable for several reasons. For example, samples of pure blood-free amniotic fluid obtained during intra-operative amniocentesis at cesarean section were diluted with 0.9% saline and serial dilutions were tested using both tests [16,17]. The study design does not correspond to the bed-side situation where amniotic fluid is contaminated by vaginal discharge or other possible fluids like urine, semen or blood that may affect the test result causing false positives, if the test is too sensitive. A high rate of positive PAMG-1 test results has been found among patients with intact membranes and labor at term [18] and in patients with a short cervix [19]. This data has not been considered when analyzing the specificity of PAMG-1 test. Also, the publication on the intra-amniotic dye test and its comparison with the PAMG-1 test is a congress abstract only, with no information on the numbers of patients or the study design [20]. Finally, IGFBP-1 test results have repeatedly been shown to be unaffected by the presence of blood [10,21,22]. Indeed, the monoclonal antibody used in the Actim PROM test does not recognize the highly phosphorylated IGFBP-1 which is the predominant isoform in maternal and fetal blood and decidua [4]. Since blood may be present in approximately 25% of cases with suspected PROM, this information is critical in order to estimate the accuracy and clinical usefulness of the marker. Suspected rupture of membranes in the presence of bleeding is the most challenging situation in the clinic, since the therapeutic measures differ depending on whether the membranes in such a case are intact or not. Yet, no information is available on the accuracy of the PAMG-1 test in patients with suspected membrane rupture and bleeding since patients with bleeding have systematically been excluded in PAMG-1 clinical studies, suggesting that PAMG-1 test cannot be used in such challenging cases. The statement that presence of blood up to 50% does not interfere with the PAMG-1 test result is only based on a Conference Poster, reporting serial dilutions of peripheral blood in 0.9% saline in vitro [23]. Again, the study design is not equivalent to the clinical situation where amniotic fluid in cervicovaginal swab sample is mixed with vaginal secretion and other possible contaminants. Also, this high rate of positive Amnisure results in the presence of blood raises a question on the validity of the reported range in the maternal blood (0.5–2 ng/ml) that should not react in a test with a detection limit of 5 ng/ml. Considering all the points above, the currently available data does not unequivocally support the superiority of the PAMG-1 test as compared with the IGFBP-1 test.
Richard G Forbes - One of the best experts on this subject based on the ideXlab platform.
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physical explanation of the universal separation 3 law found numerically for the electrostatic interaction between two protruding nanostructures
2018Co-Authors: Richard G ForbesAbstract:This Conference Poster relates to the electrostatic interaction between (a) a “central” nanostructure standing on one of a pair of widely separated parallel planar plates of large lateral extent, and (b) a distant nanostructure standing on the same plate. The effect of the distant nanostructure is to reduce the apex field enhancement factor for the central nanostructure from the value it would have in the absence of the distant nanostructure. Using the Floating Sphere at Emitter Plate Potential (FSEPP) model to represent a pair of identical post-like structures, Forbes showed that, at large separations, the fractional reduction fell off as the inverse third power of the sphere separation. De Assis and Dall'Agnol used numerical solution of Laplace’s equation to investigate six different kinds of distant nanostructure and concluded that the inverse third-power law was a universal law. This Poster uses first-principles arguments, based on the physics of electrostatic depolarization effects associated with dipoles, to show that this universal law is expected. Further, it is suggested that arguments of this kind apply on any scale and can also be applied to macroscopic objects.
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the theory of electrostatic field ionization and implications for field electron emission theory
2015Co-Authors: Richard G Forbes, Jonathan H B DeaneAbstract:This Conference Poster presents the results of a re-derivation, using the modern International System of Quantities (i.e., mksa equations), of a formula for the rate-constant for the electrostatic field ionization (ESFI) of a hydrogen atom. This problem was first examined many years ago by Landau and Lifshitz, but their atomic units proof did not generate a formula of the kind required in modern technological contexts. More important for field electron emission (FE), the re-derivation also (a) illuminates three-dimensional aspects of the “attempt frequency” form of the rate-constant formula for tunneling processes from bound states, and (b) raises doubts as to the universal correctness of current methods of using quasi-classical (JWKB-like) methods to discuss FE from non-planar emitters.