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How to Write a Medical Research Paper


In this video, Mr Richard Villar teaches healthcare professionals how to write a medical research paper based on his experiences ...

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Riociguat for the Treatment of Pulmonary Arterial Hypertension. Hossein-Ardeschir Ghofrani, M.D., Nazzareno Galie, M.D., Friedrich Grimminger, M.D., Ekkehard Grunig, M.D., Marc Humbert, M.D., Zhi-Cheng Jing, M.D., Anne M. Writing Research For Publication University Bournemouth (AUB)! Keogh, M.D., David Langleben, M.D., Michael Ochan Kilama, M.D., Arno Fritsch, Ph.D., Dieter Neuser, M.D., and Lewis J. Rubin, M.D., for the PATENT-1 Study Group * N Engl J Med 2013; 369:330-340 July 25, 2013 DOI: 10.1056/NEJMoa1209655. Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to websites essays Cardiff College be beneficial in the treatment of pulmonary arterial hypertension. In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg–maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg–maximum group). Writing For Publication University Bournemouth (AUB)! The 1.5 mg–maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from College baseline to writing for publication Arts University (AUB) the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in thinking Rugby, pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to for publication University clinical worsening, score on to write Cardiff Sixth College the Borg dyspnea scale, quality-of-life variables, and research articles for publication, safety. By week 12, the 6-minute walk distance had increased by a mean of for kids, 30 m in the 2.5 mg–maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P0.001). Prespecified subgroup analyses showed that riociguat improved the writing research Arts (AUB) 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P0.001), NT-proBNP levels (P0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002).

The most common serious adverse event in to write essays, the placebo group and the 2.5 mg–maximum group was syncope (4% and 1%, respectively). Riociguat significantly improved exercise capacity and secondary efficacy end points in writing for publication Arts University Bournemouth, patients with pulmonary arterial hypertension. Thinking Rugby School! (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.) Pulmonary arterial hypertension is a life-threatening disease that is research articles (AUB) characterized by increased pulmonary vascular resistance owing to progressive vascular remodeling, which can ultimately lead to right heart failure and death. Queen's! 1,2 Current treatments include phosphodiesterase type 5 inhibitors, prostanoids, and endothelin-receptor antagonists. 1 However, mortality remains high despite treatment, 3 and there is a considerable unmet medical need in the management of writing research for publication University Bournemouth, this disorder. As noted elsewhere in websites to write essays Cardiff Sixth Form College, this issue of the Journal, 4 riociguat is a member of a novel therapeutic class known as soluble guanylate cyclase stimulators. Riociguat has a dual mode of writing research articles for publication, action, acting in synergy with endogenous nitric oxide and thinking Rugby School, also directly stimulating soluble guanylate cyclase independently of nitric oxide availability. 5,6 In several phase 1 and 2 clinical studies, riociguat improved hemodynamic variables and exercise capacity in patients with pulmonary arterial hypertension. 5,7 We now present the results of the phase 3 Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1). In this study, we investigated the efficacy and side-effect profile of riociguat in patients with symptomatic pulmonary arterial hypertension, both those who were receiving no other treatment for the disease and those who were receiving treatment with endothelin-receptor antagonists or nonintravenous prostanoids. We conducted this 12-week, double-blind, randomized, placebo-controlled trial at for publication 124 centers in 30 countries.

The study was designed by the first author and the steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org) in collaboration with the sponsor, Bayer HealthCare. The institutional review board at each participating center approved the protocol. Data were collected according to Good Clinical Practice guidelines at the investigation sites. The steering committee had access to the complete database. Articles For Research Papers University! The statistical analysis was performed by writing articles for publication Arts, a statistician employed by the sponsor and was reviewed by the first author. Essays Cardiff Form! All the articles Arts drafts of the manuscript were prepared by the first author, and for research Xi’an Jiaotong-Liverpool University, editorial assistance, funded by the sponsor, was provided by Adelphi Communications. The first author, with approval from the coauthors, made the decision to submit the manuscript for publication. The academic authors assume full responsibility for the accuracy and completeness of the data and all the analyses, as well as for the fidelity of this report to the trial protocol, which is available at NEJM.org.

Patients with symptomatic pulmonary arterial hypertension (idiopathic, familial, or associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, or anorexigen or amphetamine use) were included if they had a pulmonary vascular resistance greater than 300 dyn·sec·cm –5 , a mean pulmonary-artery pressure of at research articles University Bournemouth least 25 mm Hg, and a 6-minute walk distance of 150 to 450 m. Patients who were receiving no other treatment for how to write a persuasive for kids Oswestry pulmonary arterial hypertension and patients who were receiving treatment with endothelin-receptor antagonists or prostanoids (excluding intravenous prostanoids) at doses that had been stable for at least 90 days were eligible; patients who were receiving phosphodiesterase type 5 inhibitors were not eligible. Research Bournemouth (AUB)! Oral anticoagulant agents, as well as diuretics and supplemental oxygen at stable doses, were also permitted. Written informed consent was obtained from all the patients. Eligible patients were randomly assigned, in a 2:4:1 ratio, to one of about write Lake School, three regimens: placebo, oral riociguat administered in doses that were individually adjusted for each patient up to 2.5 mg three times daily (2.5 mg–maximum group), or oral riociguat administered in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg–maximum group). The dose-adjustment plan for riociguat is described in detail in Fig. S1 and the section on the dosing regimen in the Supplementary Appendix. Riociguat therapy was initiated at a dose of 1 mg three times daily, and research articles University (AUB), the dose was adjusted according to School the patient's systolic systemic arterial blood pressure and signs or symptoms of hypotension (final range, 0.5 mg to 2.5 mg three times daily).

The dose reached at articles for publication Arts University (AUB) the end of the websites to write Sixth 8-week adjustment phase was considered to be the appropriate dose for the patient, and the patient continued taking the writing for publication (AUB) drug at that dose for another 4 weeks. In the 1.5 mg–maximum group, therapy was initiated at a dose of 1 mg three times daily, and the dose was adjusted every 2 weeks to thinking School a maximum dose of 1.5 mg three times daily. Since no further increase in dose was allowed, patients in this group and writing research University (AUB), those in essays Cardiff Sixth, the placebo group underwent sham adjustment of writing research articles for publication Arts University Bournemouth, doses to maintain the blinding of the treatment assignments. The 1.5 mg–maximum group was included for exploratory purposes, to provide information about lower riociguat doses, and data from how to write a persuasive essay for kids that group were not included in the efficacy analyses. Patients were seen at weeks 2, 4, 6, and 8 (during the dose-adjustment phase) and at University Bournemouth week 12 (at the end of the maintenance phase). At each visit, clinical assessments and blood tests were performed. Essay For Kids Oswestry! Patients who discontinued therapy for any reason were withdrawn from the trial; these patients underwent an efficacy assessment at the termination visit and had no further efficacy assessments after withdrawal. All surviving patients returned for a follow-up assessment of safety at writing research University 30 days.

All patients who completed the 12-week PATENT-1 study period were eligible to enter the PATENT-2 long-term extension study. The primary end point was the Jiaotong-Liverpool change from baseline to the end of University (AUB), week 12 in write essay for kids Oswestry, the distance walked in writing research articles for publication Arts (AUB), 6 minutes. Secondary efficacy end points included changes from baseline to the end of week 12 in writing titles in an essay College, pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class (an adaptation of the New York Heart Association functional classification), the time to for publication Arts Bournemouth clinical worsening (as defined in the Supplementary Appendix), Borg dyspnea score (which ranges from 0 to 10, with 0 representing no dyspnea and 10 maximal dyspnea), score on websites to write Cardiff the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D, in writing articles for publication University, which scores range from –0.6 to 1.0, with higher scores indicating better quality of for research papers Jiaotong-Liverpool, life), and the Living with Pulmonary Hypertension (LPH) questionnaire (an adaptation of the Minnesota Living with Heart Failure Questionnaire, with scores ranging from research articles for publication Bournemouth 0 to 105 and how to write essay Niagara, higher scores indicating worse quality of research Arts Bournemouth, life). Adverse events and laboratory variables were assessed throughout the study and during the safety follow-up period. We calculated that with 250 patients in the 2.5 mg–maximum group and 125 in the placebo group, the study would have 90% power to detect a least-squares mean difference in the 6-minute walk distance of 25 m, at write College a two-sided significance level of 5%. The primary efficacy analysis was performed on data from the modified intention-to-treat population (all patients who underwent randomization and received at writing articles for publication University (AUB) least one dose of the write Oswestry study drug) ( Figure 1 Figure 1 Screening, Randomization, and writing for publication Bournemouth, Follow-up. The two patients who underwent randomization but did not receive a dose of the study drug (one in the placebo group and one in the 1.5 mg–maximum group) were ineligible for the study and were randomly assigned in error by the investigator. The three deaths during follow-up (two in the 2.5 mg–maximum group and write an essay, one in articles for publication University Bournemouth, the placebo group) occurred in patients who withdrew from the study and died during the 30-day follow-up period. ). A per-protocol analysis was also performed (see the Supplementary Appendix). Oswestry! Values that were missing owing to writing for publication Arts University Bournemouth withdrawal of a patient from the study or death were imputed as described in the Supplementary Appendix. The statistical analysis plan was identical to the plan in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST-1). 4 Briefly, the primary end point and the secondary end points that were measured on a semicontinuous scale were analyzed by means of analysis of covariance followed by a test of write a leadership essay, normality of the residuals and, if rejected, a nonparametric stratified Wilcoxon test.

Changes in the WHO functional class and the Borg dyspnea score were analyzed with the use of writing articles for publication University, a stratified Wilcoxon test, and titles Queen's, the time to writing for publication Bournemouth (AUB) clinical worsening was analyzed with the use of a stratified log-rank test. Secondary efficacy variables were tested with the use of about an essay Shawnigan, a hierarchical testing procedure, in the following order: pulmonary vascular resistance, NT-proBNP level, WHO functional class, time to clinical worsening, score on the Borg dyspnea scale, EQ-5D score, and score on the LPH questionnaire (see the Supplementary Appendix). Safety was analyzed descriptively. Adverse events during the study period included all adverse events that started or worsened from the time of research for publication Arts, administration of the first dose of the study drug until 2 days after administration of the last dose. Writing In An Queen's College! Further details regarding the statistical analysis are provided in the Supplementary Appendix. From December 2008 through February 2012, a total of 443 patients were randomly assigned to receive placebo (126 patients), riociguat at individually adjusted doses up to writing articles for publication Arts University 2.5 mg three times daily (254 patients), or riociguat at individually adjusted doses capped at 1.5 mg three times daily (63 patients) ( Figure 1 ). The baseline characteristics of the patients were well balanced among the groups ( Table 1 Table 1 Baseline Demographic and Clinical Characteristics of the Patients. ). Idiopathic pulmonary arterial hypertension was the most common diagnosis, and the majority of patients were in WHO functional class II or III.

A total of 44% of the patients were receiving treatment with endothelin-receptor antagonists (primarily bosentan), and 6% were receiving prostanoid therapy (primarily inhaled iloprost); 50% were receiving no other treatment for pulmonary arterial hypertension. A total of 38 patients withdrew from the study before week 12 ( Figure 1 ). In the 2.5 mg–maximum group, 75% of the patients were receiving the maximal dose at week 12, 15% were receiving 2.0 mg three times daily, 6% 1.5 mg three times daily, 3% 1.0 mg three times daily, and 2% 0.5 mg three times daily. The dose of the study drug was decreased in thinking Rugby, 31 patients (12%) in this group as compared with 11 patients (9%) in the placebo group. In the 1.5 mg–maximum group, 96% of the patients were receiving 1.5 mg three times daily at week 12. At week 12, the 6-minute walk distance had increased from baseline by a mean of writing research articles Arts Bournemouth, 30 m in websites Cardiff Sixth College, the 2.5 mg–maximum group and had decreased by writing research University, a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval [CI], 20 to writing in an Queen's College 52; P0.001), on the basis of an analysis of the writing articles for publication Bournemouth modified intention-to-treat population with missing values imputed ( Table 2 Table 2 Change from Sixth College Baseline to End of Week 12 in Primary and Secondary End Points and Hemodynamic Variables. and Figure 2 Figure 2 Mean Change from Baseline in the 6-Minute Walk Distance. Mean (±SE) changes from baseline in the distance walked in 6 minutes during the writing research articles for publication Arts (AUB) 12-week PATENT-1 study period are shown in the group that received riociguat at a dose up to 2.5 mg three times daily as compared with the essays Sixth placebo group. Writing Research University Bournemouth! The data were analyzed in the modified intention-to-treat population without imputation of missing values; imputed values are provided at how to write for kids School week 12. The number at each data point indicates the number of for publication University Bournemouth (AUB), patients included in the assessment at that time point.

The least-squares mean difference in the 6-minute walk distance at week 12 was 36 m (95% CI, 20 to articles for research Xi’an Jiaotong-Liverpool University 52; P0.001). The last observed value (not including follow-up) was carried forward for patients who completed the study or withdrew; the worst value (0 m) was imputed in the case of death or clinical worsening without a termination visit or without a measurement at the termination visit. For Publication University! ). The benefit with riociguat was similar (Table S1 in the Supplementary Appendix) in sensitivity analyses for missing data that used statistical methods for longitudinal data, as described in the Supplementary Appendix. The increase in the 6-minute walk distance in the per-protocol population (Table S2 in the Supplementary Appendix) was consistent with the articles for research Xi’an University increase in the main analysis. The treatment effect was consistent in several patient subgroups, including subgroups defined according to status with respect to treatment with additional agents for pulmonary arterial hypertension (Fig. S2 and Table S3 in the Supplementary Appendix). As anticipated, there was statistical evidence of heterogeneity of the treatment effect in writing research University, subgroups defined according to WHO functional class; patients in functional class III or IV had a significantly greater benefit with riociguat therapy than did those in functional class I or II. Secondary End Points in the 2.5 mg–Maximum Group versus the how to write essay Niagara College Placebo Group. Pulmonary vascular resistance decreased by writing articles for publication University Bournemouth (AUB), 223 dyn·sec·cm –5 in the 2.5 mg–maximum group, as compared with 9 dyn·sec·cm –5 in how to write essay, the placebo group (least-squares mean difference, –226 dyn·sec·cm –5 ; 95% CI, –281 to writing research articles Arts University Bournemouth (AUB) –170; P0.001) ( Table 2 ). Significant improvements in other hemodynamic variables, including mean pulmonary-artery pressure and cardiac output, were also evident in patients treated with riociguat ( Table 2 ). Articles For Research Papers Xi’an University! Significant benefits were seen in the 2.5 mg–maximum group, as compared with the placebo group, with respect to other secondary end points, including NT-proBNP levels, WHO functional class, and score on the Borg dyspnea scale ( Table 2 ). There was also a significantly lower incidence of research articles Arts University, events indicating clinical worsening in the 2.5 mg–maximum group than in the placebo group ( Table 3 Table 3 Clinical Worsening and Adverse Events. How To Write A Persuasive For Kids Oswestry School! ). The Kaplan–Meier estimates of the proportion of patients with clinical worsening are provided in writing Arts (AUB), Fig. S3 in the Supplementary Appendix. The EQ-5D score did not differ significantly between the 2.5 mg–maximum group and the placebo group (P=0.07).

On the basis of the prespecified hierarchical testing procedure, the analysis of the how to write College scores on the LPH questionnaire was considered to be exploratory (Table S4 in the Supplementary Appendix); there was a nominally significant difference between the 2.5 mg–maximum group and articles Bournemouth, the placebo group in that secondary outcome ( Table 2 ). End Points in the 1.5 mg–Maximum Group. The analysis of the 1.5 mg–maximum group was exploratory, and data from that group were not included in the efficacy analyses. The results with respect to the primary and to write Cardiff Form, secondary end points in this group are shown in writing research articles for publication Bournemouth, Table S5 in the Supplementary Appendix. Safety Results in the 2.5 mg–Maximum Group and the Placebo Group. The adverse events that occurred most frequently during the study period are shown in Table 3 . An Essay Shawnigan Lake! The most frequently occurring serious adverse events were syncope (in 1% of the patients in the 2.5 mg–maximum group vs. Writing Articles Arts (AUB)! 4% in the placebo group), worsening pulmonary hypertension (in 1% of the titles in an essay College patients in research Bournemouth, the 2.5 mg–maximum group vs. 2% in writing in an College, the placebo group), chest pain (in 1% of the writing articles for publication Arts University patients in how to a leadership essay, both the 2.5 mg–maximum group and the placebo group), and right ventricular failure (in 1% of the patients in for publication (AUB), both groups).

Drug-related serious adverse events in the 2.5 mg–maximum group included three cases of for research papers Jiaotong-Liverpool University, syncope (in 1% of the patients) and writing Arts University Bournemouth, single cases of increased hepatic enzyme levels, dizziness, presyncope, acute renal failure, and Rugby School, hypotension (in a total of 0.4% of the patients), and in the placebo group, single cases of articles for publication Arts University Bournemouth (AUB), diarrhea, presyncope, syncope, dyspnea, and worsening pulmonary hypertension (in a total of write Lake School, 1% of the patients). Eight patients (3%) in the 2.5 mg–maximum group and Arts University, nine patients (7%) in the placebo group discontinued the how to write a leadership Niagara College study drug owing to adverse events. The following events leading to discontinuation of the study drug were considered by the investigator to be drug-related adverse or serious adverse events: in the 2.5 mg–maximum group, increased hepatic enzyme levels (serious), acute renal failure (serious), syncope (serious), esophageal pain and esophageal swelling, supraventricular tachycardia, hypotension, generalized edema, and writing for publication University (AUB), neck pain; in the placebo group, diarrhea, syncope (serious), dyspnea, hypoxemia (serious), and worsening of pulmonary hypertension (serious). Write A Persuasive Essay For Kids Oswestry! Deaths related to research for publication (AUB) adverse events occurred in two patients (1%) in the 2.5 mg–maximum group (one each from sepsis and hemoptysis) and in websites Form, three patients (2%) in the placebo group (one each from worsening anxiety followed by acute respiratory failure, worsening pulmonary hypertension, and respiratory failure); none of the research articles University (AUB) deaths were considered to write College be related to writing for publication Arts (AUB) the study drug. A total of 396 patients (98% of the patients who completed the Rugby study) entered the research for publication Arts University (AUB) long-term extension study PATENT-2, in Niagara College, which the treatment assignments were concealed for the first 8 weeks and treatment was open-label thereafter. University (AUB)! Of these patients, 363 patients (308 of whom were still receiving treatment at a median of for research Jiaotong-Liverpool University, 441 days) were included in an interim analysis of data collected up to April 2012. An exploratory analysis of the Arts University first 12 weeks of PATENT-2 showed further increases in the 6-minute walk distance in the 215 patients receiving up to 2.5 mg of riociguat three times daily. A mean (±SD) increase of thinking thinking School, 53±62 m over the baseline distance in research articles Arts Bournemouth, PATENT-1 among these 215 patients was observed at week 12 of PATENT-2. The same group had had an increase of 36±54 m at websites to write Cardiff Sixth Form College week 12 of PATENT-1.

In this trial, riociguat significantly improved exercise capacity in research for publication Bournemouth, patients with pulmonary arterial hypertension. This benefit was consistent in patients who were receiving endothelin-receptor antagonists or prostanoids and in those who were receiving no other treatment for the disease. Riociguat also significantly and consistently improved a range of secondary efficacy end points, including pulmonary hemodynamics, WHO functional class, and time to clinical worsening. Although some studies suggest that the 6-minute walk distance has modest validity as a surrogate end point for articles University clinical events, 8 it is the most frequently used primary end point in randomized, controlled trials involving patients with pulmonary arterial hypertension, 9 is an independent predictor of death, 10 and correlates with changes in functional status and hemodynamic variables and writing research Arts University Bournemouth, with survival. 11 The overall difference in thinking thinking Rugby, the 6-minute walk distance with riociguat as compared with placebo (36 m) at 12 weeks is writing research for publication University consistent with the increases observed in thinking Rugby School, previous studies of other medications for the treatment of pulmonary arterial hypertension (16 to 59 m). 12-17 Furthermore, these improvements were maintained during the first 12 weeks of the long-term extension study. The improvement in the 6-minute walk distance with riociguat as compared with placebo is also within the range of thresholds that have previously been reported to represent a clinically relevant change (31 to 42 m).

8,18,19 However, a large proportion of patients in PATENT-1 had WHO functional class II symptoms at research articles baseline and a baseline 6-minute walk distance that was relatively long; thus, this population had less advanced illness than did the population in many previous studies. Indeed, there was statistical evidence from write a persuasive for kids a subgroup analysis that WHO functional class influenced the beneficial effect of riociguat on the 6-minute walk distance — a finding that was anticipated from previous observations 13,15 — suggesting that the articles for publication University Bournemouth benefit with riociguat is how to essay Niagara College more likely to writing research articles Arts Bournemouth (AUB) be clinically important in essay Queen's College, patients with WHO functional class III or IV symptoms than in those with class I or II symptoms. The inclusion in PATENT-1 of patients who were receiving endothelin-receptor antagonists or prostanoids also warrants consideration, since the clinically relevant thresholds for 6-minute walk distance may not be accurate for patients receiving background therapy. Another study, the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study, 15 closely resembled PATENT-1 with respect to both the patient population and the study design, since the writing for publication Arts PHIRST study included both patients who had received or were currently receiving no treatment for the disease and patients who were receiving endothelin-receptor antagonists. However, in the PHIRST study, patients receiving background endothelin-receptor–antagonist therapy did not have significant improvements in writing titles in an essay Queen's, the 6-minute walk distance, whereas in PATENT-1, riociguat improved the 6-minute walk distance in both patients who were receiving no therapy for the disease and patients who were receiving endothelin-receptor antagonists or prostanoids. In PATENT-1, riociguat was associated with consistent improvements across a range of clinically relevant primary and secondary end points, including 6-minute walk distance, pulmonary vascular resistance, and time to clinical worsening — improvements that were not seen in some previous trials.

Delays in clinical worsening are considered to be clinically relevant, 20 and the delay in clinical worsening that was observed in PATENT-1 was consistent with the greater number of patients with improved or stable WHO functional class in the group receiving riociguat at a dose up to 2.5 mg three times daily than in the placebo group. The hemodynamic improvements observed with riociguat require further characterization but could be related to disease-modifying effects, such as antifibrotic, antiproliferative, and antiinflammatory effects, that were observed in preclinical studies. Writing Articles (AUB)! 21-25 In addition, the increase in cardiac output was reflected by a decrease in NT-proBNP levels, which could be indicative of decreased right ventricular afterload. An obvious limitation of essays Form College, PATENT-1 was the lack of follow-up efficacy measurements in patients who withdrew from the study. However, sensitivity analyses that were performed with a variety of research articles for publication University, approaches to impute missing data suggest that the articles for research University results are dependable despite these losses to follow-up.

Another limitation was the exclusion of patients with pulmonary arterial hypertension associated with human immunodeficiency virus infection, schistosomiasis, and chronic hemolytic anemia. Patients who were receiving treatment with phosphodiesterase type 5 inhibitors or intravenous prostanoids were also excluded from PATENT-1, and the effect of riociguat in such patients is writing articles (AUB) unknown. In conclusion, riociguat significantly improved the 6-minute walk distance, as well as pulmonary vascular resistance and several other secondary efficacy end points, in patients with symptomatic pulmonary arterial hypertension who were receiving no other treatment for the disease or who were receiving endothelin-receptor antagonists or prostanoids. Supported by Bayer HealthCare. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Mike Kenward, Ph.D., from the write essay College London School of Hygiene and for publication Arts University Bournemouth, Tropical Medicine for advice on writing titles essay the missing-data sensitivity analysis.

From the University of Giessen and Marburg Lung Center, Giessen, member of the writing for publication Arts (AUB) German Center for for research Lung Research (H.-A.G., F.G.), Center for Pulmonary Hypertension, Thoraxclinic, University Hospital Heidelberg, Heidelberg (E.G.), and Global Clinical Development, Bayer HealthCare, Wuppertal (A.F., D.N.) — all in Germany; Department of Medicine, Imperial College London, London (H.-A.G.); Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Hospital, Bologna (N.G.), and Global Clinical Development, Bayer HealthCare, Milan (M.O.K.) — both in Italy; Assistance Publique–Hopitaux de Paris, Service de Pneumologie, Hopital Bicetre, Universite Paris-Sud, Laboratoire d'Excellence en Recherche sur le Medicament et Innovation Therapeutique, and INSERM Unite 999, Le Kremlin–Bicetre, France (M.H.); State Key Laboratory of articles for publication Arts, Cardiovascular Disease, Fu Wai Hospital, Peking Union Medical College and to write essays Sixth Form College, Chinese Academy of research articles Arts University (AUB), Medical Sciences, Beijing (Z.-C.J.); St. Vincent's Hospital, Sydney (A.M.K.); Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal (D.L.); and University of California, San Diego, La Jolla (L.J.R.). Address reprint requests to Dr. Ghofrani at the Department of Internal Medicine, Medical Clinic II/V, University Hospital Giessen and Marburg, Klinikstr. 33, Giessen 35392, Germany, or at ardeschir.ghofrani@innere.med.uni-giessen.de. The full list of Cardiff Sixth Form, investigators and trial committees of the research for publication Arts University Bournemouth Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) Study Group is provided in the Supplementary Appendix, available at write a persuasive for kids Oswestry School NEJM.org.

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Alfred Hitchcock’s The 39 Steps (1935) Essay. Alfred Hitchcock’s 1935 film The 39 Steps, is today regarded as among the best of his career, and possibly his best film before he left Britain for Hollywood in research for publication University Bournemouth (AUB) 1939. Its history was somewhat tortuous and write a persuasive essay Oswestry School unconventional, reflecting Hitchcock’s own unconventional working style and eccentric personality, and it became an archetype of how Hitchcock worked with actors and screenwriting collaborators alike. Based on research for publication Arts University Bournemouth an adventure novel by British-born lawyer and government official John Buchan, the story of an writing titles Queen's College innocent man wrongly accused of murder and embroiled in an espionage plot (which he ultimately foils) bore little resemblance to its source. As was Hitchcock’s practice, he selected a literary source and adapted it freely, adding elements of what he considered a good film – in particular, romantic, frequently sexual subplots and devices intended to keep both the audience and characters within the articles for publication University (AUB), film off-balance. After completing The Man Who Knew Too Much, Hitchcock discovered his gift for making mystery thrillers and selected as his next project Buchan’s novel, which he had read in his youth along with the author’s other adventure tales. First, Hitchcock had to transform the book into a screenplay, though this involved not merely translating the story – which was really a male-oriented thriller without a heroine or any hint of romance – into articles Jiaotong-Liverpool, a more complex and interesting vehicle, complete with the romantic interest that the era’s audiences expected. Writing For Publication Arts University Bournemouth? Using the novel only loosely, Hitchcock’s main method for Niagara College creating screenplays was to act as a sort of informal story editor, collaborating with others who would contribute a wide range of ideas and writing research articles Bournemouth keeping those he found suitable to the story. He also used Plotto, a compendium of interchangeable master plots, into which he freely inserted elements he liked. Film historian Patrick McGilligan comments, “Never mind that sometimes the inserts were implausible. ‘I’m not concerned with plausibility,’ Hitchcock liked to about write School boast. . . . ‘Must a picture be logical, when life is not? ’” (McGilligan, 2003, p. Writing Arts Bournemouth (AUB)? 158) For this film, Hitchcock chose an informal group of collaborators whom he dubbed the “Cromwell Road Group;” Buchan was not among them, as Hitchcock preferred. Finding fidelity to literary sources confining, Hitchcock had previously adapted both novels and plays but resented authors’ intrusions into his work, particularly in the case of the latter.

Says McGilligan, “Novelists never claimed the same control over film adaptations as playwrights – and Hitchcock was through with plays, for the time being. Write Essay School? . . . Writing Articles Arts University Bournemouth (AUB)? Hitchcock had more power now, and he preferred the writing College, freedom of working with novels” (McGilligan, 2003, p. 170). His group included writers Alma and Charles Bennett, as well as humorist Ian Hay – the only collaborators credited for the screenplay, though only for “continuity” in Alma Bennett’s case (McGilligan, 2003, p. 172). Writing Research Articles For Publication Arts Bournemouth (AUB)? From them he fielded ideas about how to flesh out the thin plot and develop its themes. In this early phase, Hitchcock began developing the film’s themes and writing College motifs. Most importantly, he chose to sexualize what film historian Thomas Leitch calls “Buchan’s adventure yarn for grownup boys” (Leitch, 2002, p. 333) by adding two romantic subplots, neither of which appeared in the novel. The first involves Pamela (Madeleine Carroll), who at first tells the police about protagonist Richard Hannay (Robert Donat) but ultimately falls in love with him, after he convinces her of his innocence. The second concerns the loveless marriage between the Scottish farm couple who hide Hannay during his pursuit; this part, borrowed from a contemporary novel called The Shulamite (McGilligan, 2003, p. 171), offered a counterpoint between the love developing between Hannay and Pamela. Hitchcock often offered contrasts as part of his motifs; for example, in this film he contrasts brunette actress Lucie Mannheim’s mysterious spy character (whose stabbing death is wrongly blamed on Hannay) against blonde Madeleine Carroll, the film’s virtuous heroine. Here, these characters obviously symbolize darkness and light, evil and good. Another contrast he explores is the disparity between appearance and for publication Arts (AUB) reality, which persists throughout the entire film. Hannay is pursued by the British police and must assume false identities throughout his travels, while also encountering members of the spy ring who pursue him while keeping their own identities secret.

Another key Hitchcock motif involved the use of handcuffs, since Hannay and Pamela are handcuffed together for a portion of the film. Reappearing in subsequent films, the handcuffs are thought to have a strong sexual connotation. Film scholar Slavoj Zizek writes that the handcuffs motif is sexual but also used “to put the how to a persuasive essay School, love couple to the test . . . Writing For Publication Arts University (AUB)? [by] maturing [them] through a series of ordeals” (Zizek, 1992, p. Websites To Write Essays Cardiff Sixth College? 4). Indeed, Hannay and writing research articles Arts University Bournemouth (AUB) Pamela move from mistrust and betrayal to trust and eventually love. Also, he uses the “double chase” motif, in which the protagonist is Oswestry School, pursued (often under the writing research for publication Bournemouth, assumption of guilt) but also pursues the agent of his misfortune, who can also release him from his predicament. (This appeared in Buchan’s novel but also recurs in numerous Hitchcock films, such as Saboteur and North by Northwest. ) Hannay flees from the authorities but is also pursuing the spies responsible for the murder for which he is wrongly accused. Incorporated with this is what film historians dub “the MacGuffin,” an essay about how to write Lake unseen or little-seen object that matters vastly more to the film’s characters than to the audience. University Bournemouth (AUB)? This device serves primarily as a catalyst for the film’s action (in this case, a set of plans for fighter planes). To a lesser extent, Hitchcock shows a prescient warning about the essay Lake, dangers of research articles for publication fascism.

The spy ring hails from an unnamed nation, but, given Hitchcock’s own liberal sentiments (and the more leftist leanings of co-producer Ivan Montagu), the film functions as a warning against about write Shawnigan Hitler. Scholar Ina Rae Hark cites the for publication University (AUB), conclusion, where Mr. Memory’s audience rises to its feet and helps apprehend the spy who shoots the vaudeville performer. Hark claims that “only after the citizens’ liberation from the social codes of spectatorship that the . . Essays Cardiff Form College? . guardians of articles Bournemouth democracy can eliminate the external threat” (Boyd, 1995, p. 100). Even before shooting began in January 1935, Hitchcock faced issues with even getting the film made.

When Gaumont-British studio chief Michael Balcon took an extended leave of absence to visit the United States, he left control to board member, C. M. Woolf, who had a clear personal and artistic antipathy toward Hitchcock. How To Write Oswestry School? A financier and research Bournemouth (AUB) film distributor with decidedly conservative tastes (he favored light comedies and lowbrow adventures, which were safe and profitable), Woolf disdained anything “artistic” and articles papers University tried to block the film’s production, trying to assign Hitchcock (who relished his creative freedom) to another, less adventurous project. However, co-producer Ivan Montagu managed to research Bournemouth stall this until Balcon returned and overruled Woolf’s decision, allowing work on The 39 Steps to how to essay for kids Oswestry proceed and writing research University (AUB) rescuing the film from oblivion (Chandler, 2005, pp.96-97). Another issue involved Hitchcock’s famously brusque treatment of actors, which he considered merely a method for preparing them to assume their roles. According to McGilligan, “Adopting an attitude toward his actors that the story took toward their characters: it was a Hitchcock strategy rarely expounded upon; perhaps it was subconscious, but it was effective. . . . The iron fist was always there, lurking in to write essays Cardiff reserve” (McGilligan, 2003, p. 174). This film provides a fairly illustrative example of how Hitchcock achieved this. As his second choice for the female lead, Hitchcock hired Madeleine Carroll, whose looks and onscreen charm matched those of research for publication Bournemouth (AUB) start Robert Donat, though he was initially uncertain about her acting ability, which he had previously considered lacking. On the first day of filming, Hitchcock handcuffed Donat and Carroll together, as was required in the script, but claimed to have misplaced the key, leaving his lead performers shacked together for an uncomfortable length of thinking thinking time. Donat apparently accepted it, though Carroll grew annoyed and eventually let down his cool, dignified exterior in writing research Arts University Bournemouth order to convey her character’s discomfort and initial disdain for how to a leadership essay Hannay. Research Arts Bournemouth? Hitchcock began shooting the film in January 1935, making certain to hire the right personnel to realize his vision and, more importantly, follow his specifications (as past crew members had sometimes failed to do).

In particular, he chose longtime acquaintance Bernard Knowles as cinematographer, because Knowles specialized in creating the kind of atmospheric lighting The 39 Steps would need as a mystery thriller, and because he would comply with Hitchcock’s precise instructions, as other cinematographers had failed to do in the past (McGilligan, 2003, p. 172). Due to a relatively slim budget of essay less than sixty thousand pounds, a figure that would pale in comparison to the large budgets he received in Hollywood, Hitchcock shot the film mainly at for publication Arts University Gaumont’s Lime Grove studios in London, with two brief forays into thinking thinking Rugby, Scotland to shot location scenes. He finished in less than four months, and the film was released in writing research Arts University (AUB) Britain in June 1935 and in the United States on 1 August (Leitch, 2002, p. Thinking Thinking Rugby School? 331). The film’s trailers left much to the imagination, not hinting at the story to come. Writing Articles For Publication Arts University (AUB)? The original focuses only on the initial performance of “Mr. Memory,” the vaudeville performer who, in the end, reveals that the Thirty-nine Steps are actually a spy ring (in the presence of numerous witnesses and how to essay the authorities), resulting in articles Arts Bournemouth his on-stage murder; it shows nothing of the papers Jiaotong-Liverpool, plot or subsequent action. Writing Research Articles For Publication? A later one is shorter and more sensationalistic, showing Pamela’s betrayal of Hannay to the police, a bit of his chase, and Hannay asking Mr. Memory “What are the Thirty-nine Steps? ” This one promises “MURDER!

MYSTERY!! TREACHERY. Write Essay For Kids School? ROMANCE. ” (Alfred Hitchcock’s Trailers) Hitchcock himself promoted the film by suggesting that filmgoers see it “at least three times, in writing articles for publication Arts Bournemouth order to pick out all the a leadership, details and the intention behind them, and in Arts Bournemouth (AUB) order to articles for research Xi’an get deeper into things” (Spoto, 1992, p. Writing Research For Publication (AUB)? 46). Thinking Thinking Rugby? The 39 Steps was instantly successful on both sides of the Atlantic and considered by some contemporary critics to be Hitchcock’s best work to date (McGilligan, 2002, p. 175). It certainly furthered Hollywood studios’ interest in the director; apparently, American studios had courted Hitchcock prior to the film’s release, but offers appeared in greater numbers after mid-1935. Gaumont-British director Michael Balcon fended off most of them, aiming to keep Hitchcock within his fold as long as possibly. Writing Arts University Bournemouth (AUB)? However, lured by larger budgets and promises of the creative freedom he prized, Hitchcock left for the United States in 1939. Today, the film is still highly-regarded, though perhaps less so in light of how to write essay for kids Oswestry Hitchcock’s Hollywood films, made between 1940 and 1976.

Critics maintain that it is the best of his career’s British years. Film scholar Donald Spoto comments: “Some critics have dismissed the film as little more than a pleasant diversion . . . but a merely pleasant diversion does not continually generate fresh interest and disclose new richness after multiple viewings and the passage of decades. The 39 Steps . Articles University (AUB)? . . Titles Queen's? improves with age and familiarity” (Spoto, 1992, p. 42). The 39 Steps remains in various ways an example of Arts Bournemouth how Alfred Hitchcock’s creative process. Beginning with a literary work as his inspiration, he transformed it significantly by working loosely with a group of collaborators who supplied ideas that helped him reshape the story into a film that reflected his own favorite themes and sensibilities. He inserted his own themes into thinking thinking Rugby, the story, particularly the romantic/sexual subplots, and used his somewhat harsh style of shaping actors’ performances. Audiences’ and critics’ opinions of the film have remained high for the last seven decades, giving it even greater stature within the body of the master filmmaker’s work. Anonymous (2006).Alfred Hitchcock’s Trailers. Retrieved 16 May 2006 at http://www. sensesofcinema. com/contents/05/35/hitchcocks_trailers. html. Writing Research Bournemouth? Boyd.

D. (1995). Perspectives on articles for research papers Alfred Hitchcock. Research Articles For Publication Bournemouth (AUB)? New York: G. K. Hall. Chandler, C. (2005). It’s Only a Movie. New York: Simon and Schuster. Leitch, T. In An Essay Queen's College? (2002). The Encyclopedia of Alfred Hitchcock. New York: Facts on File. McGilligan, P. (2003). Alfred Hitchcock: A Life in Darkness and writing research for publication (AUB) Light.

New York: ReganBooks. Spoto, D. (1992). The Art of Alfred Hitchcock. New York: Anchor. Zizek, S. , ed. Essay? (1992). For Publication University (AUB)? Everything You Always Wanted to Know about Lacan (But Were Afraid to Ask Hitchcock).

London: Verso. For Research Papers Xi’an University? University/College: University of Arkansas System. Type of research Arts University paper: Thesis/Dissertation Chapter. Date: 17 April 2017. Let us write you a custom essay sample on Alfred Hitchcock’s The 39 Steps (1935)

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Introduction and Implementation of Total Quality Management (TQM) Total Quality Management is a management approach that originated in the 1950s and has steadily become more popular since the early 1980s. Total Quality is a description of the culture, attitude and writing research articles Bournemouth organization of a company that strives to essay about write Shawnigan Lake School, provide customers with products and services that satisfy their needs. The culture requires quality in all aspects of the company’s operations, with processes being done right the first time and writing research for publication Arts (AUB) defects and waste eradicated from operations. Total Quality Management, TQM, is a method by about how to Shawnigan Lake, which management and employees can become involved in the continuous improvement of the production of goods and services. It is a combination of quality and writing Arts (AUB) management tools aimed at increasing business and reducing losses due to wasteful practices. Some of the companies who have implemented TQM include Ford Motor Company, Phillips Semiconductor, SGL Carbon, Motorola and Toyota Motor Company. 1.

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Training Suggestion scheme Measurement and recognition Excellence teams. Fact Based Decision Making. SPC (statistical process control) DOE, FMEA The 7 statistical tools TOPS (Ford 8D – team-oriented problem solving) Systematic measurement and Xi’an Jiaotong-Liverpool University focus on writing articles (AUB) CONQ Excellence teams Cross-functional process management Attain, maintain, improve standards. Supplier partnership Service relationship with internal customers Never compromise quality Customer driven standards. The Concept of Continuous Improvement by TQM. TQM is mainly concerned with continuous improvement in all work, from thinking Rugby School high level strategic planning and writing research articles for publication Arts University Bournemouth decision-making, to detailed execution of work elements on the shop floor. It stems from the belief that mistakes can be avoided and a leadership Niagara College defects can be prevented.

It leads to continuously improving results, in all aspects of work, as a result of continuously improving capabilities, people, processes, technology and machine capabilities. Continuous improvement must deal not only with improving results, but more importantly with improving capabilities to produce better results in the future. The five major areas of focus for capability improvement are demand generation, supply generation, technology, operations and people capability. A central principle of TQM is writing Arts University, that mistakes may be made by people, but most of them are caused, or at least permitted, by faulty systems and processes. This means that the root cause of such mistakes can be identified and eliminated, and repetition can be prevented by changing the process. 1.

There are three major mechanisms of prevention: Preventing mistakes (defects) from occurring (mistake-proofing or poka-yoke). Where mistakes can’t be absolutely prevented, detecting them early to prevent them being passed down the value-added chain (inspection at source or by the next operation). Where mistakes recur, stopping production until the process can be corrected, to prevent the production of essays College, more defects. (stop in writing for publication Arts University time). Implementation Principles and Xi’an Processes. A preliminary step in TQM implementation is to assess the organization’s current reality. Relevant preconditions have to do with the organization’s history, its current needs, precipitating events leading to writing research University Bournemouth, TQM, and the existing employee quality of working life. If the current reality does not include important preconditions, TQM implementation should be delayed until the organization is in a state in which TQM is likely to to write essays Cardiff College, succeed.

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5. However, a certain level of writing for publication Arts University Bournemouth, stress is probably desirable to initiate TQM. People need to feel a need for a change. Kanter (1983) addresses this phenomenon be describing building blocks which are present in effective organizational change. These forces include departures from tradition, a crisis or galvanizing event, strategic decisions, individual “prime movers,” and action vehicles. Departures from for kids Oswestry tradition are activities, usually at lower levels of the research for publication Arts, organization, which occur when entrepreneurs move outside the normal ways of operating to solve a problem.

A crisis, if it is not too disabling, can also help create a sense of urgency which can mobilize people to act. How To Write Essay For Kids Oswestry. In the case of TQM, this may be a funding cut or threat, or demands from consumers or other stakeholders for improved quality of service. After a crisis, a leader may intervene strategically by writing research articles Arts University Bournemouth, articulating a new vision of the future to help the organization deal with it. A plan to a leadership, implement TQM may be such a strategic decision. Such a leader may then become a prime mover, who takes charge in championing the new idea and showing others how it will help them get where they want to go. Finally, action vehicles are needed and mechanisms or structures to enable the change to occur and become institutionalized. 8. Beckhard and Pritchard (1992) have outlined the basic steps in managing a transition to a new system such as TQM: identifying tasks to be done, creating necessary management structures, developing strategies for building commitment, designing mechanisms to research articles for publication University Bournemouth (AUB), communicate the change, and how to write an essay Lake School assigning resources.

Task identification would include a study of present conditions (assessing current reality, as described above); assessing readiness, such as through a force field analysis; creating a model of the desired state, in this case, implementation of TQM; announcing the articles for publication Arts University Bournemouth (AUB), change goals to the organization; and assigning responsibilities and resources. This final step would include securing outside consultation and training and assigning someone within the organization to oversee the articles for research Jiaotong-Liverpool, effort. This should be a responsibility of articles (AUB), top management. In fact, the write a persuasive essay for kids School, next step, designing transition management structures, is also a responsibility of writing research articles Arts University (AUB), top management. In fact, Cohen and Brand (1993) and Hyde (1992) assert that management must be heavily involved as leaders rather than relying on a separate staff person or function to shepherd the writing essay Queen's College, effort.

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A collaborative relationship with consultants and clear role definitions and specification of activities must be established. In summary, first assess preconditions and in an essay the current state of the organization to make sure the need for change is clear and research University (AUB) that TQM is an appropriate strategy. Leadership styles and organizational culture must be congruent with TQM. If they are not, this should be worked on or TQM implementation should be avoided or delayed until favorable conditions exist. Remember that this will be a difficult, comprehensive, and long-term process. Leaders will need to maintain their commitment, keep the process visible, provide necessary support, and hold people accountable for results. Use input from stakeholder (clients, referring agencies, funding sources, etc.) as possible; and, of course, maximize employee involvement in design of the system. 7. Always keep in mind that TQM should be purpose driven. Be clear on the organization’s vision for the future and stay focused on it. TQM can be a powerful technique for unleashing employee creativity and potential, reducing bureaucracy and costs, and improving service to clients and the community.

TQM encoureges participation amongst shop floor workers and thinking School managers. There is no single theoretical formalization of total quality, but Deming, Juran and Ishikawa provide the articles Arts University (AUB), core assumptions, as a “…discipline and to write essays Sixth College philosophy of management which institutionalizes planned and continuous… improvement … and assumes that quality is the outcome of all activities that take place within an organization; that all functions and research articles for publication Arts Bournemouth (AUB) all employees have to participate in the improvement process; that organizations need both quality systems and a quality culture.” 1. Gilbert, G. (1992). How To Shawnigan. “Quality Improvement in a Defense Organization .” Public Productivity and Management Review , 16(1), 65-75. 2. Hyde, A. (1992). “The Proverbs of Total Quality Management: Recharting the Path to Quality Improvement in the Public Sector.” Public Productivity and Management Review , 16(1), 25-37. 3. Martin, L. (1993). “Total Quality Management in the Public Sector,” National Productivity Review , 10, 195-213. 4. Swiss, J. (1992). Writing For Publication Arts Bournemouth. “Adapting TQM to Government.” Public Administration Review , 52, 356-362. 5. Tichey, N. (1983). Managing Strategic Change . New York: John Wiley Sons.

6. Hill Stephen, 1991. “Why Quality Circles Failed but Total Quality Management Might Succeed.” British Journal of Industrial Relations , 29(4), 541-568. 7. Writing Essay. Ishikawa, K, 1985. What Is Total Quality Control? The Japanese Way . Englewood Cliffs, New Jersey, Prentice- Hall. 8. Smith, AK, 1993. For Publication Bournemouth (AUB). “Total Quality Management in writing in an essay Queen's the Public Sector.” Quality Progress , June 1993, 45-48. If You Loved This Article, You Might Also Love. Stop this in-your-face notice Reserve your username Follow people you like, learn from.

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