This study was conducted to evaluate the efficiency of resin infiltration to improve the color of white spot lesions (WSLs) and to estimate the effect of different numbers of etching and resin infiltrant applications on the color change of WSLs with various depths. Ninety-six sound extracted premolars were subjected to acid attack inducing different depths of WSLs. Using a DIAGNOdent, teeth were divided into four main groups according to the depth of the WSLs: shallow enamel, deep enamel, shallow dentine, and deep dentine without cavitation. Then each of the main groups was subdivided into four groups: six teeth each with different protocols of resin infiltration as follows: 1 etching + 1 infiltrant application (EA), 1 etching + 2 infiltrant applications (EAA), 2 etchings + 1 infiltrant application (EEA), 2 etchings + 2 infiltrant applications (EEAA). Spectrophotometric analysis was measured at baseline (T0), after inducing the WSLs (T1), and following resin infiltration application (T2) for each group.P < 0.001), when compared with the clinically detectable threshold (ΔE = 3.7). While in deep enamel, EAA showed the least mean color change (1.95 ± 0.4), with P < 0.001 when compared with the critical value. Also, in shallow dentine, the least mean change was noticed with EAA (3.0 ± 0.45), with P < 0.001 when compared with the clinical color detection threshold. Furthermore, in deep dentine, EAA had the least mean difference (3.76 ± 0.6) but with no significant difference, when compared with the clinically detectable threshold.In shallow enamel, EA produced the least mean color difference (1.62 ± 0.85), with high significant difference (As the WSL got deeper, the color of the lesion became more clinically visible. In shallow enamel, the best treatment option was one etching with one resin infiltrant application. For deep enamel and shallow dentine, one etching with two applications of infiltrant gave the best lesion masking. In deep dentine, it is advisable to perform one etching with two infiltration steps, taking in consideration that all deep dentine lesions without cavitation were partially masked, remained clinically detectable, and might require more invasive restorative procedures. A beautiful smile, the most interactive communication skill of a person, is created with pleasing inherent proportions to one another and a pleasing tooth arrangement in harmony with the gums, lips, and face of the patient . Early ePrompt diagnosis and treatment are essential to avoid these lesions from turning into cavities . The ear2 + (∆a*)2 + (∆b*)2]1/2, giving a single number as a value for color difference (∆E) [Spectrophotometry aims to specify color by taking accurate measurements expressed either quantitatively or graphically. The Commission Internationale de l’Eclairage (CIE) developed a system that calculates the difference between two colors using a formula (∆E = [(∆L*)nce (∆E) . Most stnce (∆E) . Previounce (∆E) , 21, theRecently, with the advancing of materials, the infiltration concept was introduced in the field of dentistry. The purpose of the resin infiltration technique is to micro-invasively infiltrate the inter-crystalline spaces of enamel with polymerizable low viscous resin to arrest enamel lesions. Before a WSL can be infiltrated, it must be acid-etched to remove the hypermineralized pseudo-intact surface layer of enamel and thus permits resin infiltration into the body of the lesion , 23. Sin. Neuhaus and coworkers [In the 70s, Robinson et al.  investigoworkers  showed tMeyer-Lueckel and Paris  and Liu Up to our knowledge, this study was the first in the literature to evaluate the effect of different numbers of etching and resin infiltrant applications on the color change of WSLs with various depths. The null hypothesis was that different depths of WSL will have the same response of color change when using different times of etching and infiltrant applications.α = 0.05 using G-power software [A sample size of 96 human premolars, with six teeth per group, was required to estimate clinical average change of color at various WSL depths, with a power of 80% and software , 35.Ninety-six human premolars extracted for orthodontic purpose were collected from subjects treated in the Department of Orthodontics, Faculty of Dentistry, Alexandria University. Teeth were divided into four main groups according to the depth of the induced WSL: shallow enamel (SE), deep enamel (DE), shallow dentine (SD), and deep dentine (DD) without cavitation. Then each of the main groups was further subdivided into four groups, six teeth each according to the resin infiltration protocol applied. The different infiltration protocols used were one etching with one infiltrant application (EA), one etching with two infiltrant applications (EAA), two etchings with one infiltrant application (EEA), and two etchings with two infiltrant applications (EEAA).Criteria for selection: 1—sound teeth free from caries, 2—intact buccal surface with no visible cracks, stains, or hypoplastic areas, 3—no pretreatment with chemical agents.3, 3 mmol/l NaH2PO4, and 1 mmol/l CaCl2) at 37 °C and pH 7 to simulate the oral environment [Following extraction, all teeth were cleaned with tap water and stored in artificial saliva solution  colorimetric analysis was carried out on all teeth by means of a spectrophotometer , according to the Commission Internationale de L’Eclairage (CIE) L*a*b* system  at pH 5 for a whole day [All teeth were then immersed in a solution that contains 200 ml artificial caries solution  every day. Teeth were immersed again in an artificial caries solution if the extent of the lesion was not enough.The readings of induced WSLs in the outer and inner half of the enamel ranged between 10 and 25.The readings of induced WSLs present in the outer and middle of the dentine without any signs of cavitation ranged between 26 and 37.According to the readings of the DIAGNOdent™  teeth weThe color of the teeth in each group was spectrophotometrically measured after induction of the white spot lesions (T1).1 etching + 1 infiltrant application (EA).1 etching + 2 infiltrant applications (EAA).2 etchings + 1 infiltrant application (EEA).2 etchings + 2 infiltrant applications (EEAA).Each of the main groups was subdivided into four groups, six teeth each according to the resin infiltration protocol used:12.15% HCL (ICON-Etch) was applied for 2 min, then rinsed off with water spray for 30 s and dried. The number of etching applications was determined according to the group assigned.Ethanol (ICON-Dry) was applied for 30 s followed by air-drying.ICON-Infiltrant was applied and left on the tooth surface for 3 min. Excess resin was wiped away by a cotton roll and then light-cured for 40 s. In the groups with double resin infiltrant application, the application of infiltrant resin was repeated for 1 min and then light-cured for 40 s. Finally, the roughened enamel surface was polished using composite resin polishing discs and polishing cups.ICON®  resin infiltration was applied on the induced white spot lesions according to the manufacturer’s instructions:13.The color of the teeth in each group was again spectrophotometrically measured after application of ICON® (T2).The steps of the study are illustrated in Fig. To reduce the measuring error, two readings per tooth were taken for each time point. The reading was verified when the color difference between the readings obtained did not exceed the threshold of 1 ΔE unit. Readings with a difference of ΔE more than 1 unit were rejected and new readings were taken. An average of the two measurements was used when a difference of ΔE more than 1 unit persisted.t test to compare the mean color difference ΔE to the threshold of clinical detection ΔE = 3.7. In order to compare the mean ΔE between the groups, one-way analysis of variance (ANOVA) was performed followed by post hoc test. The significance level was set at P < 0.05.The data was collected and entered into the personal computer. Statistical analysis was done using Statistical Package for Social Science Version 20  software. After the data was tested for normality, it was decided to use one sample P < 0.05), while the deep dentine group showed high significant difference (P < 0.001).Table There was clinically detectable WSLs in all of the groups, as all of them exceeded the threshold of clinical detection ΔE = 3.7 as shown in Fig. P < 0.001), when compared with the critical value, except for EEAA.Table P < 0.001), EEA showed significant difference (P < 0.05), and lastly, EEAA revealed no significant difference, when compared with the clinically detectable threshold.In addition, Table P < 0.05) and EAA revealed high significant difference (P < 0.001), when compared with the critical value ΔE = 3.7.Table P < 0.05) and EEAA showed high significant difference (P < 0.001), when compared with the clinical detectable threshold.Table P < 0.001) when compared with EEAA with a mean difference of 1.374 and significantly different (P < 0.05) when compared with EAA and EEA with mean differences of 0.785 and 0.853, respectively. Those mean differences were obtained from subtraction of the respective means presented in Table Table P < 0.001) when compared with EEA and EEAA with mean differences of 1.027 and 1.194, respectively. Upon comparing EA with the rest of the modalities, significant difference (P < 0.05) was found between them.While in deep enamel, it was found that all the comparisons were significant except for EEA with EEAA. EAA gave high significant difference (P < 0.001) was found when comparing EA with EEA and EEAA with mean differences of 0.274 and 0.638, respectively. Also, high significant difference (P < 0.001) was found when comparing EAA with EEA and EEAA with mean differences of 0.824 and 1.188, respectively.Table P < 0.001) with mean differences of 1.935, 2.201, and 1.232, respectively. Also, high significant difference (P < 0.001) was found upon comparing EA with EEA with mean difference of 0.703. Furthermore, significant difference (P < 0.05) is shown when comparing EA with EAA with a mean difference of 0.266 and when comparing EAA with EEA with a mean difference of 0.969. The best resin infiltration protocols in the different depths of WSLs are demonstrated in Fig. Whereas in deep dentine, it was found that all the resin infiltration protocols show significant difference when compared with each other. When comparing EEAA with EA, EAA, and EEA, there was a high significant difference (Results in this study showed that there was a difference between the initial color of the tooth and its color after the induction of the WSL. The deeper the WSL, the more clinically apparent it was. Also, as mean ∆E exceeded 3.7 units, the lesion got deeper. Shallow enamel lesions were clinically detectable although they were insignificant when compared with the critical value. When the four groups were compared spectrophotometrically, deep dentine showed the highest color difference.A previous study by Gray and Shellis  showed iAlso, eight groups were assigned for double infiltrant application: 3 min for the first step and further 1 min for the second step according to manufacturer’s instructions. This was suggested by two studies , 33 whicTwo studies by Kim et al.  and Ou eThe main goal of treatment of the WSL is to arrest the progression of non-cavitated lesions and to improve the esthetics by diminishing their opacity. Starting with lesions in the outer enamel, the depth of the WSLs was shallow and one etching with one infiltrant application gave the least mean color difference when compared to the baseline color, providing the best result, as it nearly completely camouflaged the WSL. Therefore, it is advisable to use single etching with one infiltrant application to save time and material. However, double infiltrant application with double etching gave the highest mean color difference, statistically insignificant when compared with the threshold of clinical detection. This might be related to surface roughness produced by the resin. It was postulated that the average value of the resin color difference was related to the surface roughness, which might be decreased by polishing , 40, 41.Similarly, in deep enamel, the results showed that various resin infiltration protocols displayed no clinical detection of the WSLs as they did not exceed the clinically detectable threshold; the WSLs were well masked. The least mean color difference was noticed with one etching and double infiltration modality when compared to the initial teeth color. When comparing the four modalities, double etching with double infiltrant application improved the color but not efficiently, as the mean ∆E approached the clinical detectable threshold. This might be due to the double etching step that could have led to differences in enamel prism morphology. This was proved previously by Arnold et al.  but not However, going deeper to the lesions reaching shallow dentine where the WSLs were deeper than the previous two groups of enamel lesions, larger differences in color were found when compared with teeth color at baseline. Only two groups gave the best color match to the baseline; one etching step with either one or two infiltrant applications, their values did not exceed the clinical detectable threshold of ∆E. This might suggest that one etching step is preferable for lesions reaching the outer layers of dentine regardless of the number of infiltrant applications that will be done. To be more precise when four groups were compared, one etching with two infiltrant applications camouflaged the WSL giving the least mean value implicating the best combination of treatment for this depth of WSL. On the other hand, double etching with double infiltrant applications gave a mean value that exceeded the critical value of ∆E, presenting the worst treatment modality.Progressing in deep dentine lesions, the WSLs were the deepest reached in this study. All the treatment modalities showed clinical detection after resin infiltration, i.e., different resin infiltration protocols were not successful in completely masking the WSLs. Furthermore, the worst result was found in double etching with double infiltrant application and the best was found in one etching with a double infiltrant application. One etching was found to be enough to open the lesion pores without weakening of the tooth, while double etching resulted in exfoliation of enamel surface in some of the samples. This finding was in accordance with that of Hammad et al.  who postIt is preferable in deep dentine lesions to first try using the infiltration resin technique in an attempt to improve the color. However, according to the results of this study, we cannot anticipate the full masking of the lesions once it reach the deep layers of the dentine. If the gained result was not satisfactory and the WSL was still clinically visible, unfortunately, the treatment mean will be diverted to more invasive restorative procedures.As the WSL got deeper, the color of the lesion became more opaque and clinically visible.Resin infiltration concept is a good technique for its chameleon effect used for different depths of WSLs.With shallow enamel, the best treatment option is to perform one etching step with one application of resin infiltrant.For deep enamel and shallow dentine, the best treatment modality is one etching step and two applications of the resin infiltrant.In deep dentine without cavitation, lesions were partially masked in all the treatment modalities and remained clinically detectable.It is not advisable to perform two etching steps as enamel exfoliation, in some of the samples, was observed especially in deeper dentine lesions.Based on the results of the current study, it can be concluded that:


Wandering spleen, as its name suggests, is a rare condition where the spleen wanders in the abdomen and is most commonly found in the inferior quadrant as a palpable mass. It can have varying presentations and commonly presents as splenic torsion and very rarely as acute pancreatitis. It is imperative not to miss this diagnosis as it can lead to life-threatening complications in the form of splenic torsion/infarction. Here we describe a rare manifestation of wandering spleen where a young female presented with recurrent episodes of acute pancreatitis. Wandering spleen is a rare condition where the spleen is not found in its normal location. It occurs secondary to developmental abnormality or acquired laxity of the ligaments that hold the spleen resulting in abnormal location of the spleen and hence affects the children and young adults especially women of child bearing age . It can A 28-year-old multiparous female presented to the Emergency Department with complaints of mild abdominal pain associated with nausea for two days. She described her pain episodes as mild in nature, located in the epigastric/left upper quadrant, nonradiating, and slight worsening with food intake. She denied fever, chills, vomiting, or diarrhea.Her past medical history was significant for a similar presentation about 6 months before when she was diagnosed with idiopathic acute pancreatitis. She denied any alcohol intake and was not on any medications or herbal supplements.On admission, she was afebrile with a pulse rate of 84 beats per minute and a blood pressure of 116/80 mm Hg. Examination of the abdomen revealed mild tenderness in the epigastric region/left upper quadrant region and also with a palpable mass in the left lower quadrant. Laboratory workup revealed elevated lipase (4337), unremarkable CBC, and, with normal liver functions tests, lipid panel and IgG panel. Ultrasound of abdomen showed minimal sludge in the gall bladder without any obvious stones. CT abdomen with contrast demonstrated a spleen in the anterior left lower abdomen, elongated pancreatic tail which was coiled in conjunction with the splenic vessels, and with mild inflammation of the pancreatic tail Figures . She impWandering spleen is a rare finding, and only a few case reports of this condition causing recurrent abdominal pain secondary to pancreatitis have been published in literature. Our patient was diagnosed with this condition after her second episode of acute pancreatitis in a span of 6 months, and she eventually underwent splenopexy to prevent further complications.The presentation is variable, and it commonly presents as splenic torsion which will be described below. A few cases are incidentally diagnosed with a palpable spleen on physical examination as the spleen lies inferiorly, and presentation can be asymptomatic if diagnosed before the occurrence of complications. It can present as recurrent abdominal pain secondary to torsion and spontaneous detorsion of the splenic pedicle . Acute pImaging findings including ultrasound or CT of the abdomen play an important role in confirming the diagnosis as the presentation of this condition is variable and ruling out splenic torsion. Ultrasound of the abdomen will locate the abnormal position of the spleen, and Doppler flow should be done in those cases to demonstrate the blood flow in the splenic vessels. The diagnosis can be complicated in certain cases when spleen can be located in the normal position at the time of the imaging especially if the imaging is delayed . This isManagement depends on the presentation with splenectomy reserved for those with evidence of splenic infarction secondary to torsion. Splenopexy with splenic preservation is usually the choice for young patients without significant splenomegaly or evidence of splenic infarction as in our patient who eventually underwent elective splenopexy to fix the spleen in the normal location after the initial conservative management of acute pancreatitis.Wandering spleen as a cause of pancreatitis should be considered especially in children and young females who present with recurrent pancreatitis and without obvious causes for pancreatitis. It is a very rare occurrence and probably subclinical in many cases as the inflammation only involves the tail of the pancreas and hence many might not seek medical attention. This probably explains the rarity of literature published on pancreatitis in the setting of wandering spleen as opposed to that of splenic torsion/infarction. Nevertheless, the importance of recognition of this condition in those presenting with acute pancreatitis is paramount to prevent acute life-threatening complications in future with early surgical intervention.


Expansion of technologies, changing infrastructure, and dwindling resources have produced the need for health care reform and changes in clinical laboratories. The health care model will have to shift increasingly from a fee-for-service model to a value-based model. Expansion of technologies, changing infrastructure, and dwindling resources have produced the need for health care reform and changes in clinical laboratories. The health care model will have to shift increasingly from a fee-for-service model to a value-based model. Laboratories will have to focus more on evidence-based outcome studies evaluating the effects of their preanalytical and postanalytical practices on real patient outcomes. Although well-designed clinical trials and multicenter studies are needed to determine the effects of laboratory processes on outcomes, there has been concern that too few well-designed studies have been published. To help improve the quality of study design and to facilitate reporting transparency, several method statements have been developed. The Standards for Reporting of Diagnostic Accuracy Studies (STARD) initiative was recently updated, listing 30 items deemed crucial for transparent reporting of studies, thereby allowing the creation of a robust database for clinical practice guidelines. Three methods describing the assessment of the quality of data on which to base recommendations for such guidelines are also available. Close attention must be given to study design so that parameters ensuring study quality are met, thereby allowing inclusion of the study data in the formulation of evidence-based laboratory best practices guidelines. The practices of medicine and of clinical microbiology in the United States have been evolving because of a rapidly changing environment. Expansion of new and relatively expensive technologies, together with increasingly strained infrastructure and dwindling resources (including continued diminishing cost reimbursement), is pressing the need for health care reform. The model for health care is migrating from a fee-for-service model to a value-based model. In the new clinical environment and health care model, financial strategies of organizations will need to move away from a silo mentality of resistance to sharing information and resources and to focus on a collaborative structure in which medical care stakeholders work together to provide inclusive evidence-based best practices to ensure value in their work, as reflected in good patient outcomes –4. Syste–There has been concern that too few well-designed outcome studies have been published –4; it is–Due to the high prevalence of poorly designed studies, methods have been proposed to help design studies to decrease their methodological flaws. These methods provide structure to the design of studies, thereby averting information being missing for several key study parameters that are crucial to the robustness of the evidence being presented and contribute to a study’s validity . One staFirst published in 2003 and recently updated, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) initiative provides a checklist describing 30 items deemed necessary for inclusion in studies and reporting  9, 10)., 10.9, 1Understanding the techniques used to assess the quality and appropriateness of study data for inclusion in clinical guidelines may be of further help to researchers for study design. Several methods have been proposed for systematic reviews of the literature and assessments of the quality of data being published. The Centers for Diseases Control and Prevention (CDC) introduced and encouraged the development of the Laboratory Medicine Best Practices (LMBP) initiative, a systematic review process to evaluate effective quality improvement practices . AnotherThe CDC LMBP initiative was developed in part to apply transparent evidence-based methods for quality improvement and to assess the effectiveness of quality improvement practices and their impacts on patient care and outcomes. The initiative developed and championed a robust A-6 methodology, which is very useful for evaluating scientific evidence in guidance development. The American Society for Microbiology (ASM) has recognized the need to provide evidence-based guidelines to allow clinical microbiology laboratories to mature in the new health care environment. In recent years, the ASM Committee on Evidence-based Medicine has partnered with the CDC and its A-6 methodology in systematically reviewing, analyzing, and appraising up-to-date published literature on the application of laboratory methods for inclusion in evidence-based laboratory practice guidelines . Optimizhttps://www.ahrq.gov/gam/summaries/inclusion-criteria/index.html). The A-6 appraisal method provides screening criteria related to the topic, the question(s) being asked, and the practices or outcomes. The analysis rates the strength of the evidence, including study characteristics, effect size (strength of the relationships between variables), and consistency of overall quality. A quality score is given and the effect size is determined with the aid of a statistician with expertise in meta-analytical principles. The evidence data are then summarized and placed in an evidence summary table showing what information was abstracted and providing reasons why quality points were deducted.The value of a study is dependent on its ability to answer a clinical question being posed or evaluated. In formulating the initial question being considered in a study, a PICO strategy, consisting of (i) population, (ii) intervention or index test, (iii) comparator or reference test, and (iv) outcome, should be followed carefully. There are a number of ways to assess the quality of studies. The CDC A-6 systematic review cycle consists of six steps, i.e., (i) ask the question, (ii) acquire the evidence, (iii) appraise individual studies for inclusion, (iv) analyze the evidence, (v) apply the recommendations, and (vi) assess the impact. The third and fourth steps  focus on the evaluation of studies and the robustness of the data in them, involving screening by at least two expert reviewers. The method is based on validated evidence-based systematic review methods used in clinical medicine ; it meetIn appraising and analyzing a study, reviewers must be able to assess what was planned, what was actually done, and what conclusions were drawn. Studies are rated on three primary sequential components of the study, i.e., its quality, its effect size(s), and its outcome measurement relevant to the review question . ImportaThere are four dimensions that define study quality that reviewers rate, including (i) the study, (ii) the practice, (iii) the outcome measure, and (iv) the findings or results. Each dimension is rated separately, with each having a maximum number of points and adding up to 10 points total for each study . Points are deducted for each dimension by reviewers if expected quality parameters are not met, and justification for each deduction is documented. A rating of zero in any one of four categories excludes the study from further consideration.Dimension 1 regards the study (maximum of 3 points). The primary question asked is whether the results of the study can be generalized to other laboratories, looking at the study setting and the sample characteristics. If the study is unique to the study facility and setting, then points are deducted from its rating to gauge whether there is a likelihood that the results obtained would be achievable in other settings or laboratories. A study’s uniqueness may be in its study design, the time period, or the sample with respect to representativeness, which is a judgment regarding whether the results obtained through the study design are likely representative of the results of the practice.Bias, defined as a systematic difference in an observed measurement from the true value, may be found in many forms. Analytical bias, methodological bias, diagnostic review bias, incorporation bias, and partial verification bias are only some forms of bias that can be introduced into studies . PotentiDimension 2 represents the practice (maximum of 2 points). The intervention includes the practice being assessed. The practice should be described well enough to meaningfully distinguish it from other practices and to clarify its requirements and characteristics. Adequacy of the practice is measured through its (i) content, (ii) implementation, (iii) population/setting, (iv) training, (v) requirements, (vi) cost, and (vii) staff responsibility for practice and implementation.Dimension 3 is the outcome (maximum of 2 points). The outcome includes the impact or effect of what is being measured. The outcome measure should capture the result of implementing the practice. Evaluation criteria for an outcome measure focus on whether a measure is valid for capturing the outcome in question. The criteria also question whether methods of recording results actually provide appropriate and accurate assessment of the practice’s impact.Dimension 4 describes the findings or results (maximum of 3 points). Criteria for assessment of results focus on (i) sample sufficiency, (ii) appropriateness of statistical analysis, and (iii) uncontrolled deviations, along with result or conclusion biases. If the sample size is too small or the measurement period is too short to adequately capture rare occurrences as well as common occurrences, then the measure may provide an inaccurate representation of the effect of the practice. Even with common events, considerable variation may occur over time. Thus, the measurement period should be long enough to provide adequate and appropriate estimates of the practice’s impact. Appropriate statistical analysis should be used for the data accumulated.It is evident that medicine, together with laboratory support, has evolved and will continue to evolve dramatically over this decade and the next. Evidence-based medical practice has become the central focus for diagnostic and therapeutic directions; laboratory support will require a value-added model rather than a cost-per-test reimbursement perspective. To streamline appropriate diagnostic and therapeutic approaches to achieve good patient outcomes while maintaining economic stewardship, it is important to develop evidence-based laboratory and clinical guidelines and to continually measure the continuum of care. Formulated guidelines are only as good as the study data from which they are derived. It is time to carefully reflect on the design of studies to answer specific questions and to report the results of such studies with transparency and completeness. The available methods  should be used to assess the robustness and accuracy of studies being designed, so as to provide adequate study parameters to make the reported results meaningful for developing clinical practice guidelines.


Rb, and then switching to the reanalysis data of ERA-Interim in the outer region through the interpolated transition bandwidth of Wb. In hybrid model I, Rb and Wb were fixed because the time-varying radius of the maximum wind speed was determined by the typhoon formula. In hybrid model II, these parameters were determined to minimize the mean difference between the reanalysis data and the fields obtained by typhoon formula in the transition band at each time step of the typhoon track. The hindcasting of eight significant typhoon events approaching Tokyo Bay was performed. This validated the proposed methods in comparison with the observed storm surge anomalies. Both models performed satisfactorily. Hybrid model II was found to be superior in terms of the balance of accuracy and preparation cost.Reanalysis data and a parametric typhoon model formula are often used to prepare wind and pressure fields for storm surge hindcasting. However, their optimum selection and usage have not been well established. To enhance the accuracy of wind and pressure fields, two hybrid methods were proposed by applying a parametric typhoon model of Mitsuta–Fujii’s formula, which is determined from the typhoon center to a certain radius of  In particular, storm surges are considered to be the most significant coastal disasters at the bay head where Tokyo Port and large commercial and residential areas are situated. According to a report by Chiba Prefecture Government8, the highest possible storm surge anomaly is projected to be 5.7 m at the bay head. The typhoon in the 6th year of the Taisho era (1917) caused one of the historical storm surges in Tokyo Bay, resulting in overflow of the coastal defense system and leading to extensive damage to properties and a loss of more than 1,300 lives1.Tokyo Bay is a semi-enclosed coastal sea in the Greater Tokyo area, one of the largest city areas in the world, with a population of over 37 million Fig. . Tokyo B9, Fujita formula10, Jelesnianski formula11, Myers formula12, Mitsuta–Fujii formula13 (M–F), and Holland formula14. In these models, the maximum wind radius (rmax) that controls the maximum wind speed is a key parameter in determining the wind field, specifically the peak wind speed which could be estimated using several empirical formulae17. In contrast, the long-term reanalysis wind data obtained from data assimilation models has been widely used for storm surge hindcasting owing to its global availability and convenience. The data provided by the National Centers for Environmental Prediction (NCEP)19, European Center for Medium-Range Weather Forecasts (ECMWF)21, and Japanese Reanalysis (JRA)23 are the most commonly used reanalysis datasets. However, previous studies28 have shown that the wind speeds obtained near the typhoon center from the reanalysis data cannot accurately reproduce the observed wind fields. Thus, modifications are needed. Chao et al.26 proposed a framework to blend data from NCEP’s operational Global Forecast System (GFS) with that from a higher-resolution hurricane prediction model and successfully demonstrated an appropriately blended wind field for the typhoon-generated wind-wave prediction. However, the proposed method seems complex and impractical. Shao et al.27 presented two critical values as applicable ranges for ECMWF reanalysis wind data and Holland formula application for typhoon events that occurred in the South China Sea and East China Sea. With these two critical values, a weighting coefficient was given to combine two sets of wind data; however, the weighting coefficient was not clearly explained. Pan et al.28 proposed a similar superposition method and applied it to Typhoon Fanapi and Typhoon Meranti in 2010 by analyzing the cross-calibrated multi-platform (CCMP) reanalysis wind data. However, their method was not validated in storm surge hindcasting.The accuracy of wind and atmospheric pressure data is important to storm surge hindcasting. A wide variety of parametric typhoon models have been developed to reproduce realistic atmospheric pressure and wind fields during typhoons or tropical cyclones, such as the Takahashi formula29 (JMA). Using the created atmospheric boundary data, hindcasting of two historical storm surges in Tokyo Bay was performed using the unstructured-grid Finite Volume Community Ocean Model30 (FVCOM 4.1), which has been applied to storm surge computations in several studies37.Thus, the objective of this study is to propose a practical method for creating accurate wind and atmospheric pressure fields by blending a reanalysis dataset and a parametric typhoon formula. The widely used ERA-Interim wind and atmospheric pressure reanalysis dataset (ERA-I) and M–F model were employed. Two hybrid methods for creating the fields were proposed; their performances were validated using the observed meteorological data provided by the Japan Meteorological AgencyThe remainder of this paper is organized as follows. In Section 2, two hybrid methods are described and validated by comparison with the observed wind and atmospheric pressure fields, and the storm surge hindcasting is performed for the cases of Typhoon 8506 (the 6th typhoon in 1985) and Typhoon 1115 (the 15th typhoon in 2011) in Tokyo Bay, demonstrating the performance of the proposed hybrid methods. Section 3 presents the discussion and conclusions. Section 4 presents materials and methods.Rb and the transition bandwidth of Wb, a generalized hybrid method is proposed where the M–F model is applied in the 0 ≤ r ≤ Rb region and switching to ERA-I in the r ≥ Rb + Wb region (outer region of the transition band) while interpolating the two models in the transition band of Rb < r < Rb + Wb. In Section 2.2, this generalized idea (hybrid model II) is introduced with a method to determine the Rb and Wb parameter values. Before that, as a special case, hybrid model I is introduced in Section 2.1 by applying the M–F model in the region between the typhoon center (r = 0) and the applicable boundary, r = rmax, and switching to ERA-I in the region where r ≥ 2rmax. ERA-I and M–F model were smoothly interpolated in the transition band of rmax < r < 2rmax.By introducing the radius of FB is the resultant wind velocity component in x or y direction, or the atmospheric pressure, FM−F and FERA are the wind velocity or atmospheric pressure from M–F model and ERA-I, respectively, r is the distance between the target location and typhoon center, and rmax is given by equation  and observed (JODC) wind speeds are shown in Supplementary Fig. r = Rb from the typhoon center to the inner side of the transition band and the bandwidth Wb were investigated from r = 0 until r ≤ Lmax (Lmax is the maximum searching length) to minimize the mean value of the differences between ERA-I and M–F model across the computational grids within the transition band. For simplicity, a variable of the searching increment, Δr, was introduced where Rb = (m − 1)Δr (m is an integer number and 1 ≤ m ≤ n) and the maximum integer number of n was determined to satisfy (n − 1)Δr = Lmax − Wb  as suggested by hybrid model I.The increment value of ΔComparisons between the computed winds  and the JODC measured data during Typhoon 8506 and Typhoon 1115 are shown in Supplementary Fig. Fihb−I, is the wind velocity value or atmospheric pressure at the ith time step during a certain typhoon computed by hybrid model I, FiJODC,, is the corresponding measured wind speed or atmospheric pressure, and N is the total number of typhoon time steps. Supplementary Table To further evaluate the performance of hybrid models I and II, eight selected typhoon cases were analyzed, and their corresponding root mean square errors (RMSE) were calculated by:The hybrid model II concept was then applied to the atmospheric pressure fields, which is also vital in enhancing the storm surge computation accuracy. Comparisons of the time series of atmospheric pressures at Station Tokyo and Station Yokohama for Typhoon 8506 and Typhoon 1115 between ERA-I, Myers formula, hybrid model II, and observed data are shown in Supplementary Fig. To validate the performance of the proposed hybrid models for wind and atmospheric pressure fields, a hindcasting of storm surges in Tokyo Bay was performed using the finite volume community ocean model (FVCOM) forced by the wind and pressure data of ERA-I, M–F model with Myers formula, and the two hybrid models. To further consider the effect of possible water volume exchange between the ocean from a far place and the inner side of the bay, and also to reduce the boundary influence, a wide area was selected as the computational domain  as shown in Fig. 39, and Fig. Supplementary Table st, 1985, the observed sea level anomalies at six stations were generally higher than the mean sea level (=0). ERA-I reproduced the observed tendency better than the M–F model with Myers formula. This indicates the significant influence of the atmospheric pressure fields on the reproducibility of sea level anomalies before the typhoon approach. However, ERA-I data substantially underpredicted the storm surge peak at all six stations, which implies the insufficient spatial resolution of ERA-I data to reproduce the surge peak. Comparing all the model results, hybrid model II (for both wind and atmospheric pressure fields) performed better in reproducing the storm surge anomalies during the typhoon approach, the surge peak, and the following oscillations induced by bay-scale resonance.Supplementary Fig. Supplementary Fig. th to 9:00 on July 2nd, 1985, for Typhoon 8506, and 3:00 on September 20th to 23:00 on September 23rd, 2011, for Typhoon 1115. According to Table To further evaluate the accuracy among the six models, the RMSE (defined by equation ) betweenr = 0) and a certain radius (r = Rb), and switched to ERA-I when the radius is greater than Rb + Wb through the linearly interpolated transition band with the width of Wb. For hybrid model I, both Rb and Wb were fixed as the time-varying radius of rmax was determined by the M–F model at a distance from the typhoon center where the maximum wind speed occurred. Conversely, in hybrid model II, the optimum combination of Rb and Wb was determined to minimize the mean difference between the M–F model and ERA-I within the transition band. Thus, hybrid model II was considered to be the generalization of hybrid model I. The wind fields of the eight historical typhoon cases approaching Tokyo Bay were compared between ERA-I, the M–F model, hybrid model I, and hybrid model II. The accuracy of the typhoon wind fields calculated by ERA-I, the M–F model, hybrid model I, and hybrid model II were verified by comparison with the observed wind field provided by JODC. Results showed that while both hybrid models performed better than ERA-I and the M–F model, the accuracy of hybrid model II was higher than that of hybrid model I. The atmospheric pressure fields were also modified using hybrid model II.Parametric typhoon models and reanalysis datasets are widely used for storm surge simulation. However, only a few studies seek their optimum combination to enhance the accuracy of storm surge computation. In this study, two hybrid models were proposed for wind fields, where the M–F model was applied between the typhoon center  with future climate scenarios, e.g., scenarios discussed in Intergovernmental Panel on Climate Change (IPCC) reports. Then, these atmospheric fields can be used in place of ERA-I reanalysis data for hybrid model I and II combining with parametric typhoon model.The locations of the meteorological observation stations in Tokyo Bay and its surrounding areas are shown in Fig. Among historical typhoons and storm surges that occurred in Tokyo Bay between 1951 and 2017, 15 typhoon cases with large storm surge anomalies (greater than 0.8 m) were screened out and eight typhoons see Fig.  were selSeveral reanalysis datasets are for wind and pressure fields, including the ERA-I, NCEP-DOE reanalysis II, and parametric typhoon models. A preliminary investigation was performed on the data consistency by a comparison with observed data from eight typhoon cases obtained in Section 4.1. ERA-I and the M–F model were used because both of them were more consistent with the measured data for the eight typhoon cases in Tokyo Bay during the preliminary study. Moreover, this method is applicable to any combination of reanalysis datasets and typhoon formulas.ERA-Interim (ERA-I) is a global atmospheric reanalysis production provided by the European Center for Medium-Range Weather Forecasts (ECMWF), which started in 1979 and has since been continuously updated. In this study, ERA-I data of 6-hour interval wind speeds at a 10-m height from the mean sea level and the sea surface level atmospheric pressure were used. One-hour interval time series datasets for ERA-I were also created by interpolation. To obtain the most accurate ERA-I at the target stations, a 0.125° grid in the longitude and latitude was used.40 (JODC) at four stations during Typhoon 8506 and Typhoon 1115. When the center of Typhoon 8506 was far from Station Tokyo (1985/06/24/06:00-1985/07/01/00:00 and 1985/07/01/10:00-1985/07/03/06:00), Station Honmoku (1985/06/24/06:00-1985/06/30/18:00 and 1985/07/01/10:00-1985/07/07/00:00), and Station Shionomisaki (1985/06/24/06:00-1985/06/29/12:00 and 1985/07/02/12:00-1985/07/07/00:00), ERA-I was consistent with that of the measured JODC data. When the center of Typhoon 8506 approached Station Tokyo (1985/07/01/00:00-1985/07/01/10:00), Station Honmoku (1985/06/30/18:00-1985/07/ 01/10:00), and Station Shionomisaki (1985/07/01/00:00-1985/07/01/10:00), ERA-I was lower than that of the measured JODC data. For Typhoon 1115 and the other six typhoon cases, similar analyses were carried out.Figure rmax to 1.84 rmax (1985/7/1/0:00-1985/7/1/10:00), 3.09 rmax to 2.23 rmax (1985/6/30/18:00-1985/7/1/10:00), and 2.15 rmax to 2.44 rmax (1985/6/29/12:00-1985/7/1/12:00), respectively. With the aforementioned distances, large discrepancies between the observed data and ERA-I were noted.With the typhoon center far from the stations, the wind speeds were fairly consistent with the observed data with the corresponding approaching and departing distances between the typhoon center and Station Tokyo, Station Honmoku, and Station Shionomisaki ranging from 3.94 D1, is defined as the applicable distance limit from the typhoon center. It was proposed to identify the applicable range of ERA-I at a target location during the typhoon approach. ERA-I is applicable at a location when the distance from the typhoon center to the location is greater than D1. A similar explanation can be applied to D2, which is defined for the typhoon departure condition. The distances D1 and D2 consist of the applicable boundaries for ERA-I.After the ERA-I analysis for the eight typhoon events and the JODC observation data at eight stations, the applicable ranges for ERA-I are summarized in Table D1 and D2 values is the plotting of the time-series ERA-I data and JODC observed data at each station during the selected typhoon events. Instances with large discrepancies are then noted. The distance from the typhoon center to the station at the noted instance is finally calculated as the D1 value for this typhoon. The distance of D2 is similarly determined under the departing condition. As shown in Table D1 values. It can be seen that D1 and D2 values are approximately 2 rmax. Hence, to simplify the following analysis, D1 and D2 are set as 2 rmax.The first step in determining P(r) is the pressure at a radial distance r from the typhoon center, Pc (hPa) is the typhoon central pressure, P0 (=1013.25 hPa) is the ambient or environmental pressure, r is the distance from the computational mesh node to the typhoon center, and rmax (km) is the maximum wind speed radius.The Myers formula based on the exponential distribution of the atmospheric pressure field is given by:41, the M–F model was selected to compute the wind field as presented in equation  is the pressure field calculated by Myers formula, C1 and C2 are dimensionless coefficients ranging from 0.6 to 0.75, f is the Coriolis parameter, r is the distance from the typhoon center, ρa is the atmospheric density, and VT is the typhoon forward speed obtained from the best track data29 provided by the JMA including the typhoon center location and central pressure. The time-varying radius of the maximum wind speed, rmax, was determined as a function of central pressure, Pc, following the empirical formula17:D3 and D4 were determined for the M–F model from the typhoon center to the target location when the typhoon is respectively approaching and departing, as shown in Table D3 and D4 are approximately equal to rmax). Thus, M–F model is applicable in the area between the typhoon center (r = 0) and the boundary (r = rmax).Applying this model to the eight typhoon cases, the estimated wind speeds were compared with the observed data for Typhoon 8506 and Typhoon 1115 cases as shown in Supplementary Fig. Supplementary Information


The pathophysiology of acute coronary syndrome (ACS) involves platelet activation and thrombus formation after the rupture of atherosclerotic plaques. Thrombin is generated at the blood-plaque interface in association with cellular membranes on cells and platelets. Thrombin also amplifies the response to the tissue injury, coagulation and platelet response, so the treatment of ACS is based on the combined use of both antiplatelet  and antithrombotic drugs . Bivalirudin competitively inhibits thrombin with high affinity, a predictable response from its linear pharmacokinetics and short action. However, a present remarkable controversy exists between the latest main Guidelines in Clinical Practice and the key trials evaluating the use of bivalirudin in ACS. The aim of this review is to update the development of bivalirudin, including pharmacological properties, obtained information from clinical trials evaluating efficacy and safety of bivalirudin in ACS; as well as the recommendations of clinical Guidelines. Acute coronary syndromes (ACS) are the leading cause of death and high morbidity worldwide despite advances in pharmacological and interventional treatment. The genesis of ACS disrupts molecular mechanisms of hemostasis involving platelet activation, aggregation and thrombin generation as the final phase after activation of coagulation system . Thus, tBivalirudin is a direct thrombin inhibitor that has a near immediate effect with linear dose response, resulting in a predictable anticoagulant effect. In several studies bivalirudin reduced ischemic and bleeding events compared with heparin , but theInitiation of ACS is caused by disruption of atherosclerotic plaques and exposition of high thrombogenic matrix components that contact with platelets. These platelets present constitutive receptors (GPVI and integrin α2β1) that adhere to subendothelial collagen and von Willebrand factor (vWF) . ActivatUpon activation, platelets increase expression of anionic phospholipids on their surface and promote coagulation cascade by assembling of coagulation factor complexes. Concomitant with platelet activation and aggregation, plaque disruption exposes tissue factor (TF) expressed by lipid-laden macrophages and smooth muscle cells found in the core of the disrupted plaque that results in activation of the coagulation system ,16,17 F.Exposed tissue factor binds activator FVII and this complex activates FIX and X in the presence of calcium and their cofactors on the platelets surface FVIIIa and Va, respectively to form tenase and prothrombinase ,19. HencThrombin converts fibrinogen to fibrin serving as matrix scaffold at the vascular injury that lead to the formation of platelet-rich thrombi, the central event in the pathogenesis of ACS ,24. DuriHence, thrombus formation in the context of the ACS is coordinated by two different pathways led by platelet and thrombin . Under hThrombin presents different specific binding sites for several substrates. It contains an active catalytic site with serine residues responsible for the proteolytic cleavage of clotting factors that become activated. In addition thrombin contains a substrate recognition site, the exosite 1, which orients fibrinogen to bind thrombin to fibrin in a clot. Also, a second positively charged region, exosite 2, is the heparin-binding site .vs. 19.9%. HR 0.92, 95% CI 0.85–1.01; p = 0.07) but bleeding rates were increased .Indirect thrombin inhibitors, direct thrombin inhibitors and PAR-1 antagonists in addition to standard antiplatelet therapy have been evaluated in ACS treatment. Vorapaxar, an oral PAR-1 antagonist that inhibits thrombin-induced platelet activation, was recently investigated in patients with ACS. In their main clinical trial, TRACER trial , there wIndirect thrombin inhibitors such as UFH and low molecular weight heparin (LMWH) act by enhancing the function of antithrombin III (ATIII), which indirectly leads to inactivation of thrombin and factor Xa . UFH hasi.e., enoxaparin) treatment produces more uniform and consistent anticoagulation than UFH because it is less plasma protein binding leading to more predictable bioavailability. LMWH has more favorable pharmacokinetics and produces greater proximal inhibition of the coagulation cascade, in particular factor XA, without continuous monitoring [Because of the limitations of UFH, LMWH have emerged . LMWH  showed vs. 5.7%) with a reduction of major bleeding events . The OASIS-6 trial [vs. 114) and rates of severe bleeds were similar (9 vs. 16) but there was higher rate of guiding catheter thrombosis . Due these clinical trials, fondaparinux is recommended as anticoagulation treatment for non-STEMI patients but not for STEMI patients undergoing PCI.Fondaparinux is a synthetic pentasaccharide that binds antithrombin, resulting in a 340-fold increase in the rate of FXa inhibition over the basal rate . Two lar-6 trial  evaluateDirect anticoagulants produce inhibition of both fibrin-bound thrombin and fluid-phased thrombin with a predictable anticoagulant response . Direct In the last decade, four direct oral anticoagulants (DOACs) have emerged. These are small molecules that bind directly to their intended target, either activated factor IIa-thrombin (dabigatran) or activated factor Xa , and neutralize their activity . Their pIn atrial fibrillation (AF), DOACs have emerged as an alternative for vitamin K antagonists (VKAs) for thromboembolism prevention and they are at least as effective as VKAs in prevention ischemic stroke and also associated with fewer intracranial hemorrhages and less drug interactions ,49.p = 0.001, I2 = 0%) or PAR-1 antagonists  in addition to antiplatelet therapy with only moderate reduction of composite of death, myocardial infarction or stroke [A recent meta-analysis evaluated the role of DOACs and PAR-1 antagonists in the treatment of ACS. The study revealed an up 3-fold increased risk of hemorrhagic stroke in patients receiving DOACs  or activated partial thromboplastin time (APTT) . Severalet al. reported results in 25 patients undergoing PCI divided in three groups of different renal function . Patients received a bolus dose of bivalirudin (1 mg/kg) followed by an infusion . They also performed an independent study in eight patients with severe renal impairment receiving a bivalirudin bolus of 1 mg/kg, followed by an infusion of 0.5 mg/kg per hour for 10 h. The authors analyzed bivalirudin in plasma and urine by highly specific liquid chromatography-mass spectrometry assay. They concluded that the pharmacokinetics of bivalirudin are dependent on renal function but independent of dose and gender. Approximately 20% of unchanged drug was cleared via the kidney, and the remainder presumably underwent proteolysis intracellularly. The pharmacodynamics of bivalirudin resulted dose-dependent and gender-independent. They found bivalirudin kinetics linear in the dose ranges used in PCI, which are nowadays under controversy for use in ACS [Robson e in ACS .et al. reported a similar dose-response ratio in APTT and ACT evaluated in different groups of patients receiving between 0.6 to 2.5 mg/kg bivalirudin per hour in a clinical study including 291 patients undergoing coronary angioplasty [et al. evaluated ACT levels in 12 patients receiving 1.0 mg/kg bivalirudin per hour, followed by an infusion of 2.5 mg/kg/per hour. They reported an average ACT of 362 s at steady state and a maximal ACT levels > 300 s in all patients [A dose-ranging study performed in 55 patients with unstable angina evaluated bivalirudin dosage relationship with the prolongation of the APTT and a close correlation was reported for doses ranging from 0.25 to 1.0 mg/kg per hour. Intra- and interindividual variation coefficient ranged from 6.2%–11.9% and 11%–20%, respectively . Topol eioplasty . Anotherpatients .Since a poor relationship has been reported for the activated clotting time (ATC) or activated partial thromboplastin time (APTT) with the concentration of r-hirudin as measured by a chromogenic factor II assay, an alternative method has been proposed for hirudin derivatives. Bivalirudin can be monitored at the point of care via ecarin clotting time (ECT), a whole blood clotting assay based on the prothrombin–activated snake venom ecarin, which offers reliable on-line monitoring for direct thrombin inhibitors . This men = 9/group; placebo groups: n = 3/group) design. They determined a half-life of bivalirudin of 34 min, similar to the reported data of Caucasian patients and it can provide the desired anticoagulant effects. They reported a strong correlation between bivalirudin concentration and anticoagulant effect and established a sigmoid model to fit the pharmacodynamic parameters activated clotting time (ACT), activated partial thromboplastin time (APTT) and prothrombin time (PT) and bivalirudin concentrations. The findings of this study suggested that the same dosing regimens of bivalirudin may be administered to Chinese and Caucasian patients [Another study assessed pharmacokinetics and pharmacodynamics following intravenous administration of bivalirudin in healthy Chinese subjects equally divided into four groups of different bivalirudin dosage. The study was a randomized, single-blind and placebo-controlled  and subcutaneous administration . The intravenous infusion of hirulog showed a rapid, dose-dependent prolongation of APTT, PT, and thrombin time (TT). Plasma levels are reached within 2 min after intravenous administration and there was a corresponding dose-dependent increase in plasma hirulog levels, with absolute bioavailability between 40% and 80% [A randomized controlled clinical trial in healthy volunteers showed a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous . Also, bivalirudin achieved a lower rate of major bleedings with 4.9% vs. 8.3% . Therefore, treatment with bivalirudin as compared with UFH improved event free survival at 30 days with lower major bleeding. However, bivalirudin infusion was stopped just when coronary intervention finished, featuring a higher rate of early stent thrombosis in patients treated with bivalirudin .Bivalirudin has been studied in several randomized clinical trials in STEMI and non-STEMI patients undergoing PCI with contradictory findings . For STEpatients . This opp = 0.001) and bivalirudin reduced the risk of major bleeding . Regardless in EUROMAX trial the use of radial access site and new P2Y12 inhibitors such as ticagrelor or prasugrel was higher than previous trials, stent thrombosis was more frequent in the bivalirudin group than in control group . Although 93% of patients in bivalirudin group received a prolonged (4 h or longer) infusion of bivalirudin compared with HORIZONS-AMI trial [p = 0.007) with no significant difference in rates of subacute stent thrombosis [Similar findings were observed in the European Ambulance Acute Syndrome Angiography (EUROMAX) randomized trial. In this study, patients with STEMI were randomized to initiate bivalirudin or UFH with optional GPIs during transport in ambulance for primary PCI . All patMI trial  where thrombosis .p = 0.01). No differences were observed in the major bleeding rate, comparing bivalirudin vs UHF groups . Furthermore, the rate of early thrombosis stent was higher from bivalirudin group than for UFH group . The HEAT-PPCI trial concluded that UFH reduces the incidence of major adverse ischemic events in patients with STEMI underwent primary PCI, with lower rate of stent thrombosis and similar rates of major bleeding events compared with bivalirudin. As a result, there was a significant change in clinical guidelines for STEMI management about treatment with bivalirudin and generated mistrust between professionals regarding the use of bivalirudin.Inside this concern for early stent thrombosis, divergent findings emerged from How Effective Are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) single-center trial . The autvs. 13.2%; RR 0.67; CI 95% 0.50–0.90; p = 0.008). The 30-day bleeding rate was 4.1% for bivalirudin, 7.5% for UFH and 12.3% for UFH plus GPIs (p < 0.001) Furthermore, this is the only one of last trials that rates of acute stent thrombosis were not increased with bivalirudin . Another small trial, the Bavarian Reperfusion Alternatives Evaluation (BRAVE-4) trial analyzed the benefit of bivalirudin plus prasugrel vs UFH plus clopidogrel for STEMI patients [Then, to determinate the safety and efficacy of bivalirudin, the Bivalirudin in Acute Myocardial Infarction Versus Glycoprotein IIb/IIIa and Heparin Undergoing Angioplasty (BRIGHT) trial was conducted . Patientpatients . The trip = 0.036) and UFH-GPIs had higher minor bleeding  and transfusion  than the bivalirudin group.For non-STEMI patients, the clinical trial findings are more consistent. The first highlighted study was PROTECT-30 which evaluated the role of monotherapy with bivalirudin compared with UFH plus GPIs among patients with non-STEMI . The autvs. 13%, RR 1.12 CI 95% 0.98–1.28; p = 0.10) but the rates of major bleeding were significantly fewer in patients with bivalirudin alone (4%) among those who received UFH plus GPIs (7%) . In addition, stent thrombosis within first 30 days occurred in 1.4% patients with similar rates among the three treatment groups (p = 0.87). Thus the authors concluded that in moderate and high-risk patients with non-STEMI, anticoagulation with bivalirudin alone during PCI showed similar rate of NACE and stent thrombosis than UFH treatment with significantly lower risk of major bleeding events. In the same way, the Intracoronary Stenting and Antithrombosis research (ISTAR-REACT 4) trial analyzed the role of bivalirudin in non-STEMI patients who had underwent PCI [vs. bivalirudin alone immediately before PCI. All patients also received antiplatelet treatment with aspirin 325 to 500 mg and 600 mg of clopidogrel and underwent to invasive intervention within 24 h after admission. Importantly, radial artery access was used only in six patients. The primary endpoint at 30 days  was 10.9% in UFH-GPIs group and 11.0% in bivalirudin group . Major bleeding was lower in bivalirudin group (2.6%) compared with 4.6% in UFH-GPIs treatment  and there were no differences between definite stent thrombosis (0.6% vs. 0.7%). Therefore, UFH plus GPIs failed to reduce the primary endpoint and increased the risk of bleeding events with similar rate of stent thrombosis in non-STEMI patients.Nevertheless, the main clinical trial in non-STEMI patients was the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Non-STEMI patients  were randomized 1:1:1 to receive bivalirudin alone, bivalirudin plus GPIs or UFH plus GPIs . Of all went PCI . In thisDue to the contradictory results reported in previous clinical trials in STEMI patients, there is a change in the recommendations about the use of bivalirudin between the current and previous clinical guidelines . In 2012However, due to the findings of HEAT-PPCI trial  that UFHAs happened with clinical trials, the recommendations of management of non-STEMI patients are consistent about different clinical guidelines, with high level of evidence for use bivalirudin. NICE clinical guidelines  publisheThe new 2015 ESC guidelines for the management of non-STEMI recommend bivalirudin as an alternative to UFH plus GPIs inhibitors during PCI with class I-level A of evidence . In 2014et al. conducted the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial [vs. 10.3%, RR 0.67 95% IC 0.49–0.92; p = 0.013). Also they compared standard care of ESC guidelines with UFH plus GPIs with bivalirudin alone. Antiplatelet treatment included clopidogrel, prasugrel and ticagrelor. There were two bivalirudin groups: short bivalirudin arm, when the infusion stopped at the completion of PCI and long bivalirudin arm where the dose infusion reduced to 0.25 mg/kg/h for at least six hours. Bivalirudin was not statistically superior to UFH at 30 days for MACE  or NACE  but the superiority of bivalirudin was in reducing major bleeding. As previous trials in STEMI patients, early stent thrombosis was higher in bivalirudin group . In a post-hoc analysis of the MATRIX trial, the authors found no evidence for an interaction between the effect of radial vs. femoral access and allocation to bivalirudin or UFH treatment group for all cause mortality, MACE or major bleeding (p for interaction ≥0.64). Currently, there are no other major clinical trials, so meta-analysis were performed with the mail clinical trials for STEMI patients (sample size between 1000 and 3600 patients). Farag. et al. [vs UFH in ACS and concluded that bivalirudin increases early stent thrombosis in STEMI patients with small reduction difference in major bleeding with bivalirudin, and the reduction in major bleeding with bivalirudin is not related to vascular access site. In the same way, Bittl et al. [2Y12 blockers on the risk of bleeding and stent thrombosis during PCI. The weighted mortality rate was no different with 2.18% for bivalirudin and 2.34% with heparin . The absolute bleeding rate of 3.52% for bivalirudin was lower than the rate of patients treated with heparin (5.39%) while the absolute rate of stent thrombosis was higher with bivalirudin (1.40%) than with UFH (0.90%). In addition, the important findings of this meta-analysis was that no significant bleeding advantage of bivalirudin over UFH could be identified in randomized clinical trials with radial access  and the use of prasugrel or ticagrelor eliminated bleeding differences of bivalirudin  but did not reduce the risk of stent thrombosis in the bivalirudin arm (OR 2.20 IC 95% 1.48–3.27).In the last year, there have been new interesting publications to help us in decision-making about treatment with bivalirudin. Valgimigli X) trial . This st. et al.  performel et al.  analyzedvs drug-eluting), the lack of power P2Y12 antiplatelet treatment or absence of infusion of bivalirudin after PCI in the trials [2Y12 inhibitor reduces the bleeding advantage of bivalirudin over UFH, even when using radial access with lower rate of bleeding. Generally, STEMI patients undergo to PCI in the first 2–4 h, with simultaneous administration of antiplatelet and antithrombotic treatment. The more potent P2Y12, prasugrel and ticagrelor need at least 4–6 h after administration to achieve maximum effect. The discontinuation of bivalirudin at the end of PCI and before the onset of oral antiplatelet effect may create a vulnerable window for stent thrombosis. Future trials to evaluate definitive role of bivalirudin in STEMI patients should look for if early stent thrombosis could be mitigated by extending infusion of bivalirudin after PCI or using potent antiplatelet agents, including intravenous drugs [Old clinical trials related early stent thrombosis with the characteristics of the stent (bare metal e trials . In recee trials . Moreoveus drugs . Non-STE2Y12 drugs are needed to clarify the role of bivalirudin in STEMI patients. Until then, clinicians should evaluate thrombotic and hemorrhagic risk of ACS patients to achieve the optimal antithrombotic therapy.Thrombin plays an essential role in the genesis of acute coronary syndrome because it is involved in both platelet and coagulation system activation. Bivalirudin is an effective anticoagulation treatment with predictable linear dose response to avoid hemorrhagic events. In non-STEMI patients, clinical trials and guidelines agree on the efficacy and safety of bivalirudin over treatment with heparin in PCI. However, the evidence for STEMI patients shows more controversy presenting higher rates of early stent thrombosis, that does not compensate the reduction of bleeding events with bivalirudin. Multicenter randomized clinical trials with radial access and potent P


Community mobilisation through group activities has been used to improve women’s and children’s health in a range of low-income and middle-income contexts, but the mechanisms through which it works deserve greater consideration. We did a mixed-methods systematic review of mechanisms, enablers and barriers to the promotion of women’s and children’s health in community mobilisation interventions.We searched for theoretical and empirical peer-reviewed articles between January 2000 and November 2018. First, we extracted and collated proposed mechanisms, enablers and barriers into categories. Second, we extracted and synthesised evidence for them using narrative synthesis. We assessed risk of bias with adapted Downs and Black and Critical Appraisal Skills Programme checklists. We assigned confidence grades to each proposed mechanism, enabler and barrier.78 articles met the inclusion criteria, of which 39 described interventions based on a participatory group education model, 19 described community-led structural interventions to promote sexual health in marginalised populations and 20 concerned other types of intervention or multiple interventions at once. We did not have high confidence in any mechanism, enabler or barrier. Two out of 15 proposed mechanisms and 10 out of 12 proposed enablers and barriers reached medium confidence. A few studies provided direct evidence relating proposed mechanisms, enablers or barriers to health behaviours or health outcomes. Only two studies presented mediation or interaction analysis for a proposed mechanism, enabler or barrier.We uncovered multiple proposed mechanisms, enablers and barriers to health promotion through community groups, but much work remains to provide a robust evidence base for proposed mechanisms, enablers and barriers.CRD42018093695. Community mobilisation through group activities can improve women’s and children’s health in a range of low-income and middle-income contexts.To our knowledge, this is the first systematic review of the mechanisms, enablers and barriers to health promotion through community mobilisation.Our study uncovered 15 proposed mechanisms and 12 proposed enablers or barriers to health promotion, but found insufficient evidence for high confidence in any particular mechanism, enabler or barrier.Future community mobilisation researchers need to strengthen the evidence base for not just intervention outcomes, but also intervention contexts and processes.Community mobilisation interventions have been used successfully worldwide to improve maternal and newborn health,In Nepal, India, Malawi and Bangladesh, participatory women’s groups have been used to promote maternal and newborn health by employing a trained peer facilitator to lead group members through a cycle of prioritising, planning and implementing strategies to address local health problems.The complex nature of community mobilisation often poses problems for evaluation within standard biomedical frameworksA consensual remedy for the challenge of generalisability has often been the development of conceptually clear and empirically supported theory of how such interventions work,To address this lack of empirically supported theory, we conducted a mixed-methods systematic review of mechanisms, enablers and barriers to health promotion through community mobilisation. Given the heterogeneity of interventions,Our review sought to answer two main research questions:What mechanisms, enablers and barriers have global health researchers proposed to explain the impact of community mobilisation interventions through groups on women’s and children’s health in low-income and middle-income countries?What is the evidence on the roles of the proposed mechanisms, enablers and barriers in influencing women’s and children’s health in the same intervention contexts?We developed methods a priori, described them in a PROSPERO protocolWe searched for and extracted studies for inclusion in the review.We extracted and collated proposed mechanisms, enablers and barriers to health promotion in the included studies.We extracted evidence relating specifically to the proposed mechanisms, enablers and barriers uncovered in the previous step from the included studies.We conducted quality appraisal of the extracted evidence.We used the results from the quality appraisal and the evidence extraction in an evidence synthesis.We consulted a search librarian for databases and search terminology. We searched PubMed, Web of Science, Scopus and ProQuest for articles published in peer-reviewed journals. We chose these databases to include a broad spectrum of global health, social science and multidisciplinary outlets. PubMed and Web of Science provided articles primarily from the health and natural sciences. Scopus and ProQuest included social science and multidisciplinary outlets. We handsearched the reference lists of relevant articles and tracked citations in Google Scholar.In choosing search terms, we faced challenges. The term ‘community mobilisation’ does not have a unified definition and little agreement exists on the relationship between it and its many sister constructs: community engagement, involvement, inclusion, consultation, participation, building, coalition, organisation, development, capacity, capability, resilience, power or empowerment.We included all study designs as we expected the theory for the review to come from a broad range of publications, including review articles synthesising findings from disparate studies into overarching theories, protocol articles proposing theories of change for an intervention, and formative research for new interventions. We included studies presenting theory or evidence of a mechanism, enabler or barrier to improving women’s or children’s health through community mobilisation with community groups. We defined women’s or children’s health as women’s sexual or reproductive health, maternal, newborn, child or adolescent health, or prevention of violence against women or children. We included all target populations involving women or children, including subpopulations such as female sex workers, transgender women or orphans.We excluded articles that did not study women’s or children’s health, did not evaluate, review or conduct formative research for an intervention, did not discuss interventions involving community groups, or did not discuss any proposed mechanisms, enablers, or barriers to improving women’s or children’s health through their intervention. We also excluded articles in which community groups were not used for a health promotion purpose , were not open to general members of a target population , or were only mobilised for a single meeting .One reviewer (LG) conducted database searches and imported articles into Covidence,LG and a second reviewer (AA or AF) independently read each included study and extracted key information . In the same process, LG and AA or AF extracted proposed mechanisms, barriers or enablers of health improvement, and any theories, concepts or models referenced related to a proposed mechanism, barrier or enabler. LG met with each second reviewer to compare the extracted information and resolve discrepancies, with judgement deferred to DO and ND if consensus was not reached.LG entered a summary of the resulting consensus mechanism, barrier or enabler into a matrix. LG imported the consensus matrix into MaxQDA 2018 qualitative analysis software and collated the proposed mechanisms, barriers and enablers into overarching mechanisms, barriers and enablers. Throughout the analysis process, LG discussed his codes with AA, AF, DO and ND to ensure analytic rigour and reduce the influence of his position.LG rereviewed the included articles to extract qualitative or quantitative evidence concerning the collated mechanisms, enablers or barriers. LG only included primary studies and excluded all review, protocol, methods and theory articles. However, LG included one meta-regression,We considered qualitative or quantitative studies to provide evidence ‘for’ a mechanism, if the study found that either the intervention produced the mechanism, or the mechanism produced an intervention outcome, or both. We considered studies to provide evidence ‘against’ a mechanism if they failed to find evidence of the above. We considered studies to provide evidence ‘for’ an enabler or barrier if they found the ability of the intervention to produce its target outcomes was affected by the enabler or barrier. We considered studies to provide evidence ‘against’ an enabler or barrier if they failed to find such evidence. A column was included for studies providing mixed evidence. A second reviewer (DO or ND) checked each entry in this matrix for 10% of the studies, including the judgement of whether the piece of evidence supported or contradicted a proposed mechanism, enabler or barrier. We found no major discrepancies.LG and AF independently conducted risk of bias assessment for all articles providing evidence concerning a mechanism, enabler or barrier. They met to establish consensus in case of disagreements and deferred judgement to DO and ND if consensus was not reached. We adapted standard methods for risk of bias assessment to the context of assessing evidence for mechanism, enablers or barriers. We used the Critical Appraisal Skills Programme checklist for qualitative studiesLG conducted the evidence synthesis following WHO guidelines.In line with recent Cochrane reviews on mechanisms and contextual modifiers,Merging database searches across PubMed, Web of Science, Scopus and ProQuest yielded 3853 records. Handsearch and citation tracking yielded 20 more . After rOf these, 17 were qualitative (22%), 9 used mixed-methods (12%), 7 were randomised controlled trials (9%), 21 were observational (27%), 13 were review articles (17%), 1 was a meta-analysis (1%), 8 were study protocols (10%), 1 was a methodological paper (1%) and 1 was a theory paper (1%). As described in the Methods section, we excluded review articles, study protocols, methods papers and theory papers from evidence extraction and synthesis, but included them in theory extraction.10.1136/bmjgh-2019-001972.supp1Supplementary dataNineteen studies (24%) described community-led structural interventions, primarily associated with sex worker rights programmes in the Avahan initiative in India.Assessments of individual studies are provided in 10.1136/bmjgh-2019-001972.supp2Supplementary data10.1136/bmjgh-2019-001972.supp3Supplementary dataOf 36 studies involving quantitative evidence, 23 clearly aimed to explore mechanisms, enablers or barriers. Twenty-two studies had applied psychometric tests to validate multi-item measures where appropriate, such as calculating Cronbach’s alpha. No studies tried to account for social desirability bias in their measurement of social constructs, for example, by using list randomisation or randomised response surveys.10.1136/bmjgh-2019-001972.supp4Supplementary dataFor most of the mechanisms, the current state of evidence gave us low confidence in their role in community mobilisation. We had medium confidence in two mechanisms . We had no confidence in one mechanism  as we could not find a study providing evidence for it. No mechanism was purely studied for a specific country, intervention or health outcome.Group participation: Evidently, attendance is required for groups to form at all.Group deliberation: Qualitative evidence indicated that group members frequently shared in meetings experiences, concerns and opinions about both their own health issues and wider problems in the community,Informal information sharing: Multiple qualitative studies found that group members shared information and advice with other members and their wider social network.Informal social support: Many qualitative studies found group members engaged in informal acts of financial, emotional or practical support for community members. These included helping others access health services,Collective action: Multiple qualitative and quantitative studies found group and community members engaging in organised collective action such as awareness-raising and education campaigns, self-organised services, collective financial schemes, meetings with leadership structures, and civic marches and protests.Critical consciousness: Multiple qualitative studies described the development of critical consciousness—the ability to reflect critically on everyday reality and uncover the social roots of ill health—as a key contributor to social and behavioural change.Attitudes and norms relevant to a health issue: Qualitative and quantitative studies of interventions to prevent violence against women generally found reductions in accepting attitudes towards violent practices,Self-concept: Multiple qualitative studies reported increased self-confidence among group members as a result of gaining new knowledge, voicing opinions in public and connecting with people outside their household.Technical knowledge and skills: Qualitative studies found that groups enabled members to get a more accurate understanding of health by providing opportunities for them to pool individual knowledge through story-telling, visual games and other interactive learning activities.Practical knowledge and skills: Thirteen articles discussed improvements in practical knowledge and skills as potentially part of the intervention mechanism. Examples included ‘life skills’,Women’s position in the household: Two qualitative studies of an intervention to prevent intimate partner violence found evidence for greater female autonomy and respect for wives from husbands.Social cohesion: Multiple studies reported qualitative evidence that group members felt that their groups were based on principles of trust, solidarity and respect,Civic attitudes and norms: Multiple quantitative studies of sex worker programmes sought to relate ‘collective efficacy’—the belief that sex workers could work together to deal with shared problems—with intervention exposure and outcomes. The results were mixed and depended on the measure of collective efficacy,Self-governance: Qualitative studies emphasised the importance of community ownership of the problem-solving process and found that extensive capacity building could create a sense of ownership.Institutional linkages: Studies of participatory women’s groups found qualitative evidence of group members engaging with the health system through a range of means: supporting local village health committees, holding meetings with health providers, training traditional birth attendants and lobbying local government.We had medium confidence in most of the proposed enablers and barriers, and low confidence for two barriers . Apart from pre-existing social cohesion and inclusion of vulnerable subpopulations, no other enabler or barrier was purely studied for one specific country, intervention or health outcome. Evidence concerning pre-existing social cohesion only existed in India and evidence concerning inclusion of vulnerable subpopulations as an enabler only existed for participatory women’s groups in maternal and child health. We found no study directly linking enablers or barriers to intervention impact on health behaviour or outcomes.Pre-existing poverty: Qualitative studies reported high levels of pre-existing poverty in the target population impeded intervention efforts by reducing participant time for group activities,Supportive institutional-political context: One qualitative studyPre-existing social cohesion: Two qualitative studies reported that less cohesive communities were more difficult to mobilise due to mistrust, competitiveness and social isolation.Supportive pre-existing health beliefs, attitudesand norms: Studies of interventions to prevent violence against women reported that pre-existing beliefs and attitudes to marriage and masculinity affected men’s motivation to participate in group meetings, engage in bystander intervention and allow their wives to participate.Pre-existing power relations between community members: Multiple qualitative studies described how hierarchical power relations between community members due to inequality along lines of gender, class, age or employment obstructed intervention efforts because more powerful community members excluded less powerful ones from group meetings,Pre-existing power hierarchies between household members: Multiple studies found qualitative evidence of male partners and in-laws actively forbidding women from joining group meetings due to fears about women breaching seclusion norms, spreading gossip about their household, learning bad habits from others or becoming too independent.Staff management: Multiple studies reported qualitative evidence of poor staff management affecting intervention implementation. In two studies, poor staff morale caused either individual groups or whole programmes to be abandoned.Incentives for participation: Qualitative and quantitative studies of interventions providing material incentives found that they dramatically increased meeting attendance,Managing community relations: Qualitative studies reported that conscious effort to manage relationships with community members was key to trust and credibility. This involved hiring local people to convene group meetings,Respect for local people, knowledgeand practices: Qualitative studies have repeatedly described poor relationships between staff and community members—staff lacking an ethos of open communication and participation—obstructing intervention efforts.Relevant education tools: Multiple studies noted how the use of simple, locally appropriate, fun discussion tools such as picture cards, stories or interactive games stimulate critical thinking and enhance learning in groups.Inclusion of less powerfulsubpopulations: A mixed-methods study concluded that socioeconomic differentials in attendance at participatory women’s group meetings were small because of active measures to include less powerful subpopulations: facilitators went door-to-door to invite and persuade poor women to attend and deliberately convened meetings close to their homes at convenient times.To our knowledge, this is the first mixed-methods systematic review of mechanisms, enablers and barriers to health promotion through community groups. Our review uncovered a large number of possible mechanisms, enablers and barriers, ranging from group participation to institutional linkage, from community power relations to staff and resource management. However, the number of articles proposing a mechanism, enabler or barrier exceeded the number providing evidence for it. Eleven articles proposed inclusion of marginalised populations as an enabler of intervention impact, but only one provided evidence for it. Fifteen studies proposed improved practical skills in making decisions, solving problems and assuming leadership as a mechanism, but no articles provided evidence. Thirteen studies proposed supportive institutional-political context as an enabler, but only two studies provided evidence. Our Risk of Bias assessment did not produce high confidence in any one mechanism, enabler or barrier. We are reluctant to add to this theory-evidence gap by proposing a conceptual framework of mechanisms, enablers or barriers. Nonetheless, we believe our results gesture towards issues for policy-makers and researchers to consider.First, our review shows the complexity of successfully delivering community mobilisation interventions. Implementers might need to ensure the cooperation of local stakeholders, while simultaneously challenging unequal power structures. They might need to show respect for local values while promoting attitude and norm change. They might have to nurture community ownership over health, while promoting help-seeking from external providers. This potential need to accommodate multiple, at times conflicting, desiderata resonates with descriptions in past literature of implementers having to allow a certain degree of ‘necessary contradiction’ between ideology and practice in order for their intervention to succeed.Our review revealed clear gaps in the current evidence base. Fully 91% of studies were based in South Asia or sub-Saharan Africa, presenting a need for more studies in Latin America, East Asia and the Middle East. We found limited theory and evidence concerning social processes at the household level, as all the studies recovered focused on issues of gender equality and women’s empowerment. Future studies might be able to uncover more clues about household-level processes in community mobilisation if they complement a traditional conflict perspectiveOur review suggests improvements to strengthen theory and research methods. Despite growing momentum for realist enquiry,At the level of empirical testing, our Risk of Bias assessment showed the need for more comprehensive approaches to providing empirical evidence for context and process. Few studies attempted to account for socially desirable responses from study participants despite the often explicit intention of community mobilisers to activate positive social processes of community ownership and increased social cohesion.Given our use of explicit search terms for ‘community mobilisation’ and ‘social mobilisation’, we may have missed articles that did not label their intervention as such. Some researchers describe interventions consistent with our definition of ‘community mobilisation’ under the headings ‘community participation’ or ‘community engagement’.A sizeable proportion of studies (20%) concerned the Avahan initiative to prevent HIV/STI infections among sex workers in India. This may have weighted theory and evidence towards its assumptions and conclusions. However, all the mechanisms, enablers and barriers except two were proposed and empirically investigated for multiple countries, interventions and health outcomes. None were exclusively proposed or empirically investigated by studies from Avahan, and Avahan studies did not appear disproportionately supportive or opposed to particular mechanisms, enablers or barriers compared with studies of other interventions.Finally, only one reviewer was involved in article screening due to resource limitations, which might have resulted in relevant articles being missed.In response to past scepticism concerning the state of theory in community mobilisation research,