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In oncology, as in other clinical fields, different treatments are often approved for the same therapeutic indication. In many cases, no direct comparisons are available to inform the choice in clinical practice. In 2015, the Italian Association of Medical Oncology (AIOM) instructed a working group, including both clinicians and methodologists, to discuss the issue of the best choice among different treatments available for the same indication. The working group discussed 3 different scenarios: (1) biosimilar drugs; (2) different drugs with same mechanism of action; (3) different drugs with different mechanism of action. For each scenario, methodological issues were discussed, along with the priority for investment of resources in the conduct of clinical trials testing direct comparison. As for biosimilar drugs, the panel recommended that, following comparability exercise and approval by regulatory agencies, they should be widely used, considered that their use allows financial savings. As for different drugs (with either the same or a different mechanism of action), the panel agreed that indirect comparisons and network meta-analyses are associated with relevant risk of bias and imprecision, and direct comparisons should be encouraged. The priority of these direct comparisons should be higher when the potential differences in efficacy and/or toxicity are clinically relevant. The choice of the study design (superiority vs non-inferiority) depends on the toxicity profiles and also on the presumed difference in efficacy. Scientific societies should put pressure on public bodies to identify all the administrative and financial mechanisms useful to facilitate the conduct of trials testing direct comparisons, when needed. Decision about therapeutic equivalence can have important consequences on innovation: the availability of drugs characterised by the same effectiveness, but at a lower cost, could enable non-negligible savings of economic resources that could be used to guarantee access to innovative, high-cost drugs.

The purpose and focus of the Musculoskeletal Tumor Society is stated on the organization’s website. “The mission of the Musculoskeletal Tumor Society is to advance the science of orthopaedic oncology and to promote high standards of patient care. It does this through excellence in education and research” [1]. The 2008 MSTS meeting in Phoenix, AZ, November 6–8, 2008, and hence this symposium, follows part of the prescription, providing an excellent forum for education. The second portion of the mission statement encourages advancing orthopaedic oncology through research. The organization has enjoyed limited success in conducting or promoting research despite valiant efforts by the leaders of the Research Committee. Why? Answers come from the membership, the discipline, and the organization. The membership of the MSTS has changed dramatically over the years. The original “Piranha Club” had 18 domestic orthopaedic surgeons, of whom only one remains actively practicing surgical oncology. The roster has ballooned to over 220 members, including Candidate, Affiliate, and Emeritus Members. While this reflects successful maturation of orthopaedic oncology, it has a dilutive effect on research and possibly even clinical progress. Case volume is correlated with outcome in all other cancer systems studied to date, for disease of organs ranging from prostate to pancreas. Why shouldn’t it also be true for bone and soft tissue sarcomas? As knowledge and training disseminate, experience per surgeon inevitably declines. Smaller case loads prevent concentrated expertise. Paradoxically, the numerical expansion of our membership may have improved our ability to deliver more convenient, good quality care to more people, but it may prevent us from making substantive advances in the field. Single centers usually lack the volume to ask or answer important questions. Collaboration is essential to maintain patient numbers required to study rare diseases. Standardization of treatment protocols is essential if the cases from different centers may be combined. This requires strong-willed commitment on the part of musculoskeletal oncologists to suppress some of their individuality and cooperate. This is necessary to advance the discipline and improve patient care. Large cooperative groups (eg, Children’s Oncology Group or COG, the Southwest Oncology Group or SWOG) have failed due to their cumbersome structure and an inability to channel resources to orthopaedic problems. The greatest success has been in ad hoc collaborations such as that coordinated by the MSTS to review the outcome of patients treated by limb salvage or amputation for distal femoral osteosarcoma [2], or the Toronto Group’s prospective evaluation of prognostic genetic markers (p53 and RB) in osteosarcoma patients from six centers [3]. This symposium includes a variety of novel and informative clinical papers dealing with resection and reconstruction techniques. However, most are single center studies that should be viewed as hypothesis generating ideas. They require confirmation in larger trials involving other centers to show the results can be generalized. The levels of evidence are typically IV. There is also a deficiency in basic and translational research needed to advance the field. Clearly, more effort needs to be expended to improve the quality and generalizability of our research. Investigators and reviewers need to support cluster- and association-based comparative research efforts, clinical trials, and basic investigations. There are national initiatives in this direction. Responding to the challenge proposed by the American Academy of Orthopaedic Surgeons, the Musculoskeletal Tumor Society is trying to develop evidence-based assessments of practice. This symposium includes the Society’s first effort along those lines, summarizing the best available opinion regarding the biopsy of musculoskeletal tumors. More recently, the AAOS/ORS/NIH sponsored a workshop in Albuquerque to define the research agenda for prospective outcome studies in each orthopaedic subspecialty. Two tumor projects made the final cut of recommendations. The first was a prospective study of proximal femoral metastases, comparing internal fixation (rodding) with joint arthroplasty. The second was a long-term followup of reconstructions performed for patients randomized to receive, or not receive, muramyl tripeptide phosphoethanolamine (MTP-PE) in the national Intergroup-133 study. These projects should receive the support of the oncology community, and would be good topics on which the MSTS could focus and include in future CORR Symposia.

The AACT/EAPCCT Position Statements published between 1997 and 19991–5 were a major attempt to summarise the evidence on gastrointestinal decontamination and to develop recommendations based on this evidence. Launched with some fanfare, they were an important landmark in cooperation between European and North American societies and their conclusions have been widely cited. Seven years later, the first updated versions of the position statements are now being published.6–8 Perhaps it is time for the clinical toxicology community to take stock of what has happened in research on gastrointestinal decontamination since these position statements were published, and since they concluded that there was insufficient clinical trial evidence to support the use of any form of gastrointestinal decontamination in any situation. The strongest recommendations for changes in practice were directed against ipecac, gastric lavage, and cathartics. The use of activated charcoal more than one hour after ingestion was also strongly questioned. Undoubtedly, there have been substantial changes in practice over the last decade and the position statements have provided the necessary collegiate support for this to occur. However, implications about the need for further research that should have been drawn from these documents have not lead to an increase in high quality clinical research in this area. On the contrary, in the last seven years we believe that only three controlled clinical trials of gastrointestinal decontamination have been published. One of these has been published only in abstract,9 one was of a twelve year old trial 10 that had flaws in design and analysis,11 and one addressed the very specific question of the role of MDAC in yellow oleander poisoning.12 Therefore, unless a doctor treats oleander poisoning, the published clinical evidence has not progressed over the last seven years. The three updates published to date conclude their abstracts with ‘A review of the literature since the preparation of the 1997 ___ Position Statement revealed no new evidence that would require a revision of the conclusions of that Statement.” While not intended as such, this is a sad indictment on the progress of research in clinical toxicology, because the published evidence is very weak indeed. The methodology of the clinical trials reviewed was poor and should not preclude anyone from conducting a better designed study to address the same hypotheses. Future trials will need to pay closer attention in particular to ensuring random allocation, allocation concealment, and avoidance of selection or outcome bias. For example, the 2004 AACT/EAPCCT Position Paper on the use of ipecac syrup6 described five studies as randomized controlled trials (RCTs). In a two arm trial, randomisation ensures that there is equal probability of a patient being allocated to either arm.13 Allocation concealment then prevents prediction of allocation.14 Systematic biases occur when allocation is not concealed – if a doctor is able to predict the allocation, then s/he may decide not to recruit a patient if they would get an intervention the doctor does not favour.15 Methods to ensure this does not happen are embedded in current standards for clinical trials.16,17 Four of the cited studies used alternate day allocation18–21 – or pseudo randomisation. 13 Allocation was not ‘randomized’ because there was not an equal probability of allocation to either arm – if the patient arrived on a Wednesday, according to the protocol, s/he could only have been allocated one specific intervention. There was also no allocation concealment – the enrolling doctor knew what the patient was going to receive from the day of presentation. If the doctor’s non favoured intervention was indicated, s/he could have not recruited the patient or (if late in the day) delayed the patient in the waiting room until midnight had passed and the other intervention became available. Such practices have been recorded in many studies,13,15 and therefore pseudo-randomised studies are considered weaker evidence than RCTs. Saetta’s study did not even pseudo-randomise patients.22 The control patients in this study were specifically selected because they were considered to be either too well for gastric decontamination or presenting too late for it to have an effect.23 The surrogate primary outcome selected was also biased against the use of ipecac as the vomited tablets were excluded from statistical consideration in measuring the effectiveness of ipecac in preventing tablet movement into the small bowel. This systematic bias in selection of control patients and outcome assessment prevents any meaningful conclusion being drawn from this study.23 Similar problems of quasi-random allocation without concealment beset most studies on other methods of gastric decontamination and many have other design flaws. In order for the field to progress, it is important that the clinical studies that have been done are critically and rigorously evaluated (particularly in authoritative position papers). We sincerely commend the authors of these studies for providing the best available evidence, but we also need to critique their studies to highlight the problems and move the clinical toxicology community to provide more and better research evidence.24,25 The evidence for many interventions in clinical toxicology is weak. It will only improve if we make the first step of recognising that we have a problem.26

The medical management of inflammatory bowel disease has changed considerably over time with wider use of immunosuppressant therapy and the introduction of biological therapy. To what extent this change of medical paradigms has influenced and modified the disease course is incompletely known. To address this issue, an extensive review of the literature has been carried out on time trends of hospitalization, surgery, infections, cancer, and mortality rates in inflammatory bowel disease [IBD] patients. Preference was given to population-based studies but, when data from these sources were limited, large cohort studies and randomised controlled trials were also considered. In general, data on hospitalisation rates are strikingly heterogeneous and conflicting. In contrast, the consistent drop in surgery/colectomy rates suggests that the growing use of immunosuppressants and biological agents has had a positive impact on the course of IBD. Most clinical trial data indicate that the risk of serious infections is not increased in patients treated with anti-tumour necrosis factor alpha [TNFα] agents, but a different picture emerges from cohort studies. The use of thiopurines increases the risk for non-melanoma skin cancers and to a lesser extent for lymphoma and cervical cancer [absolute risk: low], whereas no clear increase in the cancer risk has been reported for anti-TNF agents. Finally, the majority of studies reported in the literature do not reveal any increase in mortality with immunosuppressant therapy or biologicals/anti-TNF agents.

Background Clinical efficacy of pollen allergen immunotherapy has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods pre-defined on the basis of the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen-exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert-consensus. Methods A Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen-exposure in the context of defining relevant time intervals for evaluation of efficacy in allergen immunotherapy trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered in order to achieve a consensus. Results The Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for ‘pollen season’, ‘high pollen season’ (or ‘Peak pollen period’) and ‘high pollen days’. Conclusion This EAACI position paper provides definitions of pollen exposures for different pollen types for use in Allergen Immunotherapy trials. Their validity as standards remains to be tested in future studies. This article is protected by copyright. All rights reserved.

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large-scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.

Purpose: Recent advances in computer and mobile technologies have brought increasing usages of IT technology in nursing research across nursing fields. Despite the increasing usages, there has been little discussion on methodological issues involved in nursing research using IT technology. This is a discussion paper to identify methodological issues in IT technology-based nursing research. Methods: An analysis was done using content analysis on research team meeting minutes and research team members’ research diaries in a clinical trial that tested the efficacy of a technology-based intervention. First, several major categories of IT technology-based nursing research are concisely summarized. Then, the method that was used for this analysis is presented. Results: The findings are presented as themes reflecting methodological issues in IT technology-based research: (a) difficulties in recruitment due to necessary technology literacy; (b) facilitating recruitment through allowing the use of multiple languages; (c) participants’ preferences for specific IT technology; (d) efforts needed to ensure technological security; (e) participants’ preferences for design; and (f) necessary considerations on timing. Conclusion: Finally, future directions for nursing research using IT technology are proposed based on the identified issues.

ContextTo compare family physicians' ability to retain information when reading a review article on paper vs on screen, and in their mother tongue vs in English.MethodsRandomized trial of 114 Scandinavian family physicians who read a review article in October or November 2000 from the Journal of Trauma for 10 minutes either on paper and in English, on screen and in English, on paper in their mother tongue, or on screen in their mother tongue. To assess comprehension, they immediately completed a questionnaire with 6 open questions about 13 key facts from the review article. Sum score was on a scale from 0 (no correct answers) to 13 points (all questions answered correctly).ResultsThere was no significant difference between readers of paper vs screen versions, with a median (interquartile range [IQR]) of 4 (2-6) vs 4 (2-5), respectively (P = .97). Physicians who read in their mother tongue scored significantly higher than those who read in English, with a median (IQR) of 4 (3-6) vs 3 (2-4) (P = .01).ConclusionThe medium (paper vs screen) did not influence the ability of family physicians to retain medical information. They best retained medical information when reading in their mother tongue.

Review on RCT Research Papers Related Nausea and Vomiting in Pregnancy- Focusing on Acupoint Treatment - Suk-Woo Jang, In-Suk Ahn, Min-Sun Choi, Dong-Il KimDept. of OB & GY, Dong-Guk University Ilsan Oriental HospitalObjectives: To observe randomized controlled trials(RCTs) related to invest igating the effects of acupoint treatments on nausea and vomiting in pr egnancy to establish the basis of korean medical trea tments, and suggest the problems of future clinical research. Methods: After searching for national and international papers published after 2000 and restricting the parameters to ‘clinical trial’, ‘controlled clinical trial’, ‘randomized controlled trial’, then comparing the subjects, met hods, research tools, and results to understand the effects and re-comparing the conf licting results to assume the cause. Results: Of the 9 research papers that applied acupressure, four of the m used control and experimental groups, and three(75%) research papers indicated significant reduction in vomiting and nausea, and of the seven research pap ers that utilized the experimental and placebo groups, five(71.4%) reported signi ficant reducing effects. Of the four research papers the used acupuncture treat ments, four research papers using control and placebo groups, two showed improvement s in symptoms but did not have significant results compared to sham acupunctu re groups, and two showed significant reduction of symptoms compared to the co ntrol groups. The one research paper that used electrical stimulation showed significant results in the reduction of vomiting and nausea compared to the control group. Conclusions: Acupressure and electrical stimulation showed efficacy reducing the symptoms. Acupuncture treatments did not indicate efficacy some experiments. Therefore it is thought that future acupuncture treatments shou ld use methods that resemble actual clinical medicine to establish efficacy to prod uce significant results. Key Words: Acupuncture, Acupressure, Electrical stimulation, Nausea, Vomit ing, Hyperemesis, Morning sickness

People with schizophrenia frequently have significant problems in community functioning. Progress in developing effective interventions to ameliorate these problems has been slowed by the absence of reliable and valid measures that are suitable for use in clinical trials. The National Institute of Mental Health convened a workgroup in September 2005 to examine this issue and make recommendations to the field that would foster research in this area. This article reports on issues raised at the meeting. Many instruments have been developed to assess community functioning, but overall insufficient attention has been paid to psychometric issues and many instruments are not suitable for use in clinical trials. Consumer self-report, informant report, ratings by clinicians and trained raters, and behavioral assessment all can provide useful and valid information in some circumstances and may be practical for use in clinical trials. However, insufficient attention has been paid to when and how different forms of assessment and sources of information are useful or how to understand inconsistencies. A major limiting factor in development of reliable and valid instruments is failure to develop a suitable model of functioning and its primary mediators and moderators. Several examples that can guide thinking are presented. Finally, the field is limited by the absence of an objective gold standard of community functioning. Hence, outcomes must be evaluated in part by “clinical significance.” This criterion is problematic because different observers and constituencies often have different opinions about what types of change are clinically important and how much change is significant.

Background Identifying critical life transitions in people’s physical activity behaviors may illuminate the most opportune intervention apertures for chronic disease prevention. A substantive evidence base now indicates that parenthood is one of these critical transition points for physical activity decline. This study will examine whether a brief theory-based intervention can prevent a decline in physical activity among new parents over 6 months following intervention. This study protocol represents the first dyad-based physical activity initiative in the parenthood literature involving both mothers and fathers; prior research has focused on only mothers or only fathers (albeit limited), and has shown only short-term changes in physical activity. This study will be investigating whether a theory-based physical activity intervention can maintain or improve moderate to vigorous intensity physical activity measured via accelerometry of new parents over a 6 month period following intervention compared to a control group. Methods This study is a 6-month longitudinal randomized controlled trial. Parents are measured at baseline (2 months postpartum) with two assessment points at 6 weeks (3.5 months postpartum) and 3 months (5 months postpartum) and a final follow-up assessment at 6 months (8 months postpartum). The content of the theory-based intervention was derived from the results of our prior longitudinal trial of new parents using an adapted theory of planned behavior framework to predict changes in physical activity. Results A total of 152 couples have been recruited to date. Sixteen couples dropped out after baseline and a total of 88 couples have completed their 6-month measures. Discussion If the intervention proves successful, couple-based physical activity promotion efforts among parents could be a promising avenue to pursue to help mitigate the declines of physical activity levels during parenthood. These findings could inform public health materials and practitioners. Trial registration This trial has been registered with the Clinical Trials Registry maintained by the National Library of Medicine at the National Institutes of Health on April 19, 2014. The registration ID is NCT02290808. Electronic supplementary material The online version of this article (10.1186/s12889-017-4874-7) contains supplementary material, which is available to authorized users.

OBJECTIVES A prospective parallel cohort trial was conducted to compare outcomes of patients treated with maxillary protraction vs LeFort 1 maxillary advancement surgery. SETTING AND SAMPLE POPULATION The primary site for the clinical trial is Children's Hospital Los Angeles; the satellite test site is Seattle Children's Hospital. All patients have isolated cleft lip and palate and a skeletal Class III malocclusion. MATERIAL AND METHODS A total of 50 patients, ages 11-14, will be recruited for the maxillary protraction cohort. The maxillary surgery cohort consists of 50 patients, ages 16-21, who will undergo LeFort 1 maxillary advancement surgery. Patients with additional medical or cognitive handicaps were excluded from the study. RESULTS Current recruitment of patients is on track to complete the study within the proposed recruitment period. CONCLUSION This observational trial is collecting information that will examine dental, skeletal, financial and quality-of-life issues from both research cohorts.

Background Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. Method The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). Results All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. Conclusions It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.

Pragmatic trials offer the opportunity to obtain real-life data on the relative effectiveness and safety of a treatment before or after market authorisation. This is the penultimate paper in a series of eight, describing the impact of design choices on the practical implementation of pragmatic trials. This paper focuses on the practical challenges of collecting and reporting safety data and of monitoring trial conduct while maintaining routine clinical care practice. Current ICH guidance recommends that, all serious adverse events (SAEs) and all drug-related events must be reported in an interventional trial. In line with current guidance, we propose a risk based approach to the collection of non-drug related non-serious AEs, and even serious events not related to treatment based on the risk profile of the medicine/class in the patient population of interest. Different options available to support the collection and reporting of safety data whilst minimizing study-related follow-up visits are discussed. A risk-based approach to monitoring trial conduct is also discussed, highlighting the difference in the balance of risks likely to occur in a pragmatic trial compared to traditional clinical trials, and the careful consideration that must be given to the mitigation and management of these risks in order to maintain routine care.

Background Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. Methods and Findings We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.” For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. Conclusions In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles., In a document analysis, Jeppe B. Schroll and colleagues seek insights into potential bias and underreporting in documentation of adverse events from the mid-1990s clinical trials of the anti-obesity drug orlistat., Author Summary Why Was This Study Done? Most drugs have adverse effects, or harms, that may become evident in clinical trials. Pharmaceutical companies seeking to market a new drug must report adverse effects observed in trial participants in the Clinical Study Reports (CSRs), which they provide to regulatory authorities. Additionally, investigators may report harms in published reports of their trials. We sought to understand the accuracy, and potential bias, in harms reporting for trials of orlistat, a slimming drug from Roche approved in Europe in 1998 and still marketed in Europe today. What Did The Researchers Do And Find? Using a Freedom of Information Act request to the European Medicines Agency (EMA), we obtained CSRs describing seven clinical trials of orlistat. We studied protocol instructions to investigators for reporting harms, the actual reporting of harms in individual CSR records versus summaries, and the final reporting of harms in published papers. We found that protocol instructions to trial investigators had the potential to dilute the appearance of drug-associated harms. Between 3% and 33% of the total adverse effects from CSR summaries were described in published papers. In one trial, we counted adverse events individually and found that both the number of adverse effects and the number of days with adverse effects in participants taking the drug were understated in the corresponding publication. What Do These Findings Mean? The reporting of trials of orlistat in the 1990s understated harms in the summarised results submitted to the EMA for drug approval and in the published papers. Based on the characteristics of harms observed and reported in these trials, we suggest that reports of harms include duration of adverse effects. We also suggest that systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

SummaryThe prevalence of iron deficiency is high –even in the absence of anaemia– in patients with chronic heart failure (HF). Although iron deficiency is easily diagnosed with two biomarkers (serum ferritin and transferrin saturation), it is underdiagnosed in patients with HF. Iron is not only necessary for red blood cells, but also for cells in tissues with high-energy demands (heart, muscle, brain). Even before the onset of anaemia, HF patients with iron deficiency have decreased physical and cognitive performances and a poorer quality of life. Moreover, iron deficiency is a risk factor, independent of anaemia, of unfavourable outcome (death or heart transplantation) in patients with chronic HF. Several randomized controlled studies have shown improvement in exercise capacity, New York Heart Association functional class and quality of life after correction of iron deficiency. The results of these clinical trials, which are supported by European guidelines, suggest considering iron deficiency in HF as a possible therapeutic target.

The inclusion of pharmacists in the healthcare system of a developing country like Pakistan has always been a subject of debate among the healthcare professionals (HCPs), especially physicians, who have long ruled the healthcare system alone and who have had a long-held position of supremacy. The common argument against the inclusion of pharmacists is the dynamics of the healthcare system, and patients being physician oriented, hence, consider the inclusion of pharmacists as no good. Although the trend of defiance is changing, it is worthwhile mentioning here that the concept of the inclusion of pharmacist was implemented in developed countries by an evidence-based approach, i.e., to actually involve pharmacists in the disease state management of a patient and conducting a trial. This opinion calls for the same to be implemented in a developing country like Pakistan to evaluate its significance.

Summary Background Current data from daily practice show that vitamin D3 analogues, corticosteroids and their fixed combination products are used heterogeneously for topical long-term treatment of psoriasis. Aim To evaluate scientific evidence about topical long-term therapy with vitamin D3 analogues, corticosteroids and their two-compound-products in psoriasis vulgaris and scalp psoriasis and to develop daily practice recommendations. Methods Systematic literature review via PubMed® and Embase® and informal expert consensus. Results The search strategy identified 21 relevant clinical trials. Best evidence regarding topical long term treatment was available for the two-compound-formulation containing calcipotriene and betamethasone. In a comparative trial in psoriasis vulgaris the two-compound-formulation showed superior tolerability and cost effectiveness compared to monotherapy. In scalp psoriasis the two-compound-gel was superior compared to calcipotriene monotherapy. Standardized and simplified treatment application modes resulted in a better clinical outcome comparing to on-demand therapies. Daily practice recommendations Patients should be proactively involved in the choice of treatment, formulation and mode of application. Besides long-term treatment with the two-compound-formulation other treatment regimens including calcipotriene monotherapy can also be considered. Due to a favorable risk-benefit ratio in maintenance trials and due to better cost-effectiveness the application of two-compound-products once or twice a week after initial therapy is recommended.

Insights into tumour biology of breast cancer have led the path towards the introduction of targeted treatment approaches; still, breast cancer-related mortality remains relatively high. Efforts in the field of basic research revealed new druggable targets which now await validation within the context of clinical trials. Therefore, questions concerning the optimal design of future studies are becoming even more pertinent. Aspects such as the ideal end point, availability of predictive markers to identify the optimal cohort for drug testing, or potential mechanisms of resistance need to be resolved. An expert panel representing the academic community, the pharmaceutical industry, as well as European Regulatory Authorities met in Vienna, Austria, in November 2012, in order to discuss breast cancer biology, identification of novel biological targets and optimal drug development with the aim of treatment individualization. This article summarizes statements and perspectives provided by the meeting participants.

Distal symmetric polyneuropathy (DSPN) is the most common chronic complication of diabetes mellitus. The pathogenesis of DSPN is not fully elucidated, but it is certainly multifactorial in nature and attributable to metabolic and microvessel disorders related to chronic hyperglycemia, diabetes duration, and several cardiovascular risk factors. Early diagnosis and appropriate management are extremely important, since up to 50% of DSPN cases may be asymptomatic, and patients are unaware of foot injury leading to foot ulcers and amputation. Simple, validated tests such as the Neuropathy Disability Score and/or Vibration Perception Threshold may be used to diagnose DSPN. Similarly, neurological dysfunction screening questionnaires should be used to assess the quality and severity of DSPN symptoms. Using both methods enables prediction of the prognosis of diabetic patients with DSPN. No causative treatment of DSPN is known, but the results of clinical trials indicate that several treatment options are highly effective in symptomatic treatment of painful DSPN. The appropriate treatment of DSPN may improve the outcome, preventing or delaying the development of numerous diabetic complications.

Evidence from clinical trials repeatedly confirms the association of diabetes with heart failure, independent of hypertension, atherosclerosis, coronary artery disease and valvular heart disease. However, the importance of coexistence of diabetes and heart failure is not universally recognized, despite the fact that it may significantly contribute to morbidity and mortality of the diabetic population. It seems that prevention of heart failure, early diagnosis, and appropriate management could improve the outcome. Unfortunately, the etiology of heart failure in diabetic patients is still to be elucidated. It is multifactorial in nature and several cellular, molecular and metabolic factors are implicated. Additionally, there are still no definite guidelines on either the diagnosis and treatment of heart failure in diabetic patients or on the therapy of diabetes in subjects with heart failure. This review focuses on the pathophysiology, diagnosis, and prevention of heart failure in the diabetic population as well as management of both comorbidities.

Hoon Young Suh,1 Carl C Peck,2 Kyung-Sang Yu,1 Howard Lee1,3 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea; 2Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, CA, USA; 3Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea Abstract: A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011–2013 than in 1990–2007 (31.6% vs 6.3%, P=0.036), reflecting a slow, but steady acceptance of the European Medicines Agency’s guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2–53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster. Keywords: MRSD determination method, starting dose in first-in-human study, first-in-human study with monoclonal antibody, MRSD, safety factor

Objective To evaluate the design characteristics of studies that evaluated the performance of artificial intelligence (AI) algorithms for the diagnostic analysis of medical images. Materials and methods PubMed MEDLINE and Embase databases were searched to identify original research articles published between January 1, 2018 and August 17, 2018 that investigated the performance of AI algorithms that analyze medical images to provide diagnostic decisions. Eligible articles were evaluated to determine 1) whether the study used external validation rather than internal validation, and in case of external validation, whether the data for validation were collected, 2) with diagnostic cohort design instead of diagnostic case-control design, 3) from multiple institutions, and 4) in a prospective manner. These are fundamental methodologic features recommended for clinical validation of AI performance in real-world practice. The studies that fulfilled the above criteria were identified. We classified the publishing journals into medical vs. non-medical journal groups. Then, the results were compared between medical and non-medical journals. Results Of 516 eligible published studies, only 6% (31 studies) performed external validation. None of the 31 studies adopted all three design features: diagnostic cohort design, the inclusion of multiple institutions, and prospective data collection for external validation. No significant difference was found between medical and non-medical journals. Conclusion Nearly all of the studies published in the study period that evaluated the performance of AI algorithms for diagnostic analysis of medical images were designed as proof-of-concept technical feasibility studies and did not have the design features that are recommended for robust validation of the real-world clinical performance of AI algorithms.

Objectives In this paper, we present a review of critical concepts and research perspectives and produce recommendations on the optimal use of pixantrone in non-Hodgkin lymphoma (NHL) by group discussion from an expert panel appointed by the Italian Society of Hematology and the affiliate societies, Societa Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo. Methods Recommendations were produced using the Delphi process. Scientific evidence on pixantrone efficacy was analyzed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology in the areas where at least one randomized trial was published. The following key issues were addressed for practical recommendations: pixantrone monotherapy in aggressive relapsed or refractory non-Hodgkin B-cell lymphomas and toxicity risk management in patients candidates to pixantrone. Results and conclusions After a balanced and value-oriented discussion, the panel agreed that the benefit/risk profile was in favor of pixantrone in the treatment of adult patients with multiply relapsed or refractory aggressive NHL B-cell lymphomas. Pixantrone was deemed to be contraindicated in patients with uncontrolled cardiovascular disease. Despite a low rate of cardiotoxicity of pixantrone reported in clinical trials, the panel recommended that all patients receiving pixantrone should undergo periodical cardiac monitoring.

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.

PURPOSE The aim of this study was to determine whether two methods of documentation, print and electronic forms, for the assessment of patient-reported outcomes (PRO) in complete denture wearers provide comparable results. The study also quantified the time needed for filling the forms by each method. MATERIALS AND METHODS Thirty participants enrolled in a university clinic answered two forms (a questionnaire for denture satisfaction and OHIP-EDENT). They provided answers with two application methods in a random order, with a one-month interval between them: (1) electronic forms on a tablet computer; and (2) print forms. The methods were compared in terms of mean results, correlation/agreement, internal consistency, and spent time. RESULTS Mean results for both methods were similar for each denture satisfaction item (100-mm VAS) and OHIP-EDENT summary score. Both questionnaires presented good internal consistency regardless of the application method (Cronbach's α=0.86 or higher). Correlation and agreement between the methods regarding specific items was at least moderate for the majority of cases. Mean time for the electronic and print forms were 9.2 and 8.5 minutes, respectively (paired t test, P=.06, non-significant). CONCLUSION The electronic method is comparable to print forms for the assessment of important PRO of prosthetic treatment for edentulism, considering the results and time needed. Findings suggest the viability of replacing print forms with a tablet for applying the tested inventories in clinical trials.

The use of human albumin is common in hepatology since international scientific societies support its administration to treat or prevent severe complications of cirrhosis, such as the prevention of post-paracentesis circulatory dysfunction after large-volume paracentesis and renal failure induced by spontaneous bacterial peritonitis, and the treatment of hepatorenal syndrome in association with vasoconstrictors. However, these indications are often disregarded, mainly because the high cost of human albumin leads health authorities and hospital administrations to restrict its use. On the other hand, physicians often prescribe human albumin in patients with advanced cirrhosis for indications that are not supported by solid scientific evidence and/or are still under investigation in clinical trials. In order to implement appropriate prescription of human albumin and to avoid its futile use, the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) nominated a panel of experts, who reviewed the available clinical literature and produced practical clinical recommendations for the use of human albumin in patients with cirrhosis.

No abstract available.

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.

Adoptive T-cell therapy (ACT) using expanded autologous tumor-infiltrating lymphocytes (TIL) and tumor antigen-specific T cell expanded from peripheral blood are complex but powerful immunotherapies directed against metastatic melanoma. A number of nonrandomized clinical trials using TIL combined with high-dose interleukin-2 (IL-2) have consistently found clinical response rates of 50% or more in metastatic melanoma patients accompanied by long progression-free survival. Recent studies have also established practical methods for the expansion of TIL from melanoma tumors with high success rates. These results have set the stage for randomized phase II/III clinical trials to determine whether ACT provides benefit in stage IV melanoma. Here, we provide an overview of the current state-of-the art in T-cell–based therapies for melanoma focusing on ACT using expanded TIL and address some of the key unanswered biological and clinical questions in the field. Different phase II/III randomized clinical trial scenarios comparing the efficacy of TIL therapy to high-dose IL-2 alone are described. Finally, we provide a roadmap describing the critical steps required to test TIL therapy in a randomized multicenter setting. We suggest an approach using centralized cell expansion facilities that will receive specimens and ship expanded TIL infusion products to participating centers to ensure maximal yield and product consistency. If successful, this approach will definitively answer the question of whether ACT can enter mainstream treatment for cancer. Clin Cancer Res; 17(7); 1664–73. ©2011 AACR.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [ 18 F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.

This research is part of a multi-method research program that evaluated the impact of knowledge mobilization of evidence-based information for older adults, professionals and caregivers. This research reports the results from nine caregiving clinical trials with one group of older adults, one professional group and one of carers, exposed to three levels of the intervention in each trial (n=261). The null hypotheses were that caregiving knowledge would not differ across the three conditions of no tools, paper tools or digital tools. Respondents were randomly assigned to one of three conditions for each of the three groups. The computed sample size required 29 respondents assigned to each of the three conditions for each of the three groups Respondents were tested on knowledge of caregiving pre-post. F tests showed there were significant differences across each of the three conditions. Professionals achieved higher scores with digital tools and older adults, the paper tools.

Over the past 10 years, pharmaceutical companies have found compelling reasons to use human tissue in drug discovery and development. In preclinical work, human tissue enables researchers to select and validate drug targets based on humandisease phenotypes, find inherited gene variation that contribute to disease, validate animal disease models, and reclassify disease based on molecular signature. Human tissue allows researchers to overcome some of the inherent disadvantages of animal disease models, which are often poor predictors of similar disease states in man. Also, therapeutic interventions in these animal models often do not have the same pharmacologic results seen in human clinical trials. In clinical research, use of human tissue helps medical teams segment patient populations based on biomarker profiles and thereby better target new medicines for greater patient safety and efficacy. Patients with similar clinical profiles can have different tissue pathology and disease etiology, therefore, combining standard clinical evaluations with assessment of variations in genetic expression or sequence provides clinicians with critical tools to improve patient care. Given the benefits of human tissue, many pharmaceutical companies and academic research centers are motivated to increase its use in target validation and early drug development but encounter a multitude of hurdles in the process. Use of human tissue requires rigorous patient confidentiality and data-security measures, because tissue could be used to reconstruct a patient’s genome, with potential implications for compromising privacy, insurability, and job security. 2,3,18,25 This article discusses the regulatory, pathology, information technology, and administrative issues involved in establishing, managing, and using pathologic samples from surgical specimens in a tissue bank. 22

Despite the high proportion and growing number of people with comorbidity/multimorbidity, clinical trials often exclude this group, leading to a limited evidence base to guide policy and practice for these individuals [1–5]. This evidence gap can potentially be addressed by secondary analysis of studies that were not originally designed to specifically examine comorbidity/multimorbidity, but have collected information from participants on co-occurring conditions. For example, secondary data analysis from randomized controlled trials may shed light on whether there is a differential impact of interventions on people with comorbidity/multimorbidity. Furthermore, data regarding comorbidity/multimorbidity can often be obtained from registration networks or administrative data sets. Journal of Comorbidity 2015;5(1):120–121

Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged. Key points: • Lung cancer screening using low dose computed tomography reduces mortality. • Leading US medical societies recommend large scale screening for high-risk individuals. • There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet. • The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. • High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes., SCOPUS: ar.j, info:eu-repo/semantics/published

Contains fulltext : 126210.pdf (Publisher’s version ) (Closed access) Oral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting gamma-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.

Insulin resistance, diabetes mellitus, and hypertension are associated with significant cardiovascular morbidity and mortality. Lifestyle modifications effectively decrease the risk of progression to diabetes in high-risk patients, but intensive interventions can be costly and difficult for patients to maintain. The addition of pharmacotherapy is often necessary to treat hyperglycemia and hypertension and lower the risk of cardiovascular complications. Clinical trial data suggest the use of insulin-sensitizing and antihyperglycemic agents to delay the progression to diabetes. Similarly, analysis of data from clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers indicate that the use of these agents results in fewer cases of new-onset diabetes among patients with hypertension, when compared with other antihypertensive agents. Angiotensin II has direct and indirect effects on insulin and its signaling pathways, providing support for the biologic mechanism underlying the benefits of renin-angiotensin system inhibition in preventing diabetes and cardiovascular events. Clinical trials now under way will further evaluate the role of renin-angiotensin system inhibition in preventing diabetes and its microvascular and macrovascular complications.

The CONSORT statement for the full reporting of clinical trials should be consistently applied Although current European League Against Rheumatism (EULAR)1 and American College of Rheumatology (ACR)2 guidelines both support paracetamol (acetaminophen) as the first line oral analgesic for patients with knee osteoarthritis (OA), until now there has been a paucity of clinical trial data to confirm the efficacy of paracetamol in large joint OA. This issue of the Annals is unique in containing one meta-analysis and two large placebo controlled studies that examine evidence for the efficacy of paracetamol in OA. Never in the 127 years of paracetamol’s existence have so much trial data on OA been reported. Because of the marked placebo effect in pain trials3 comparison with a placebo is clearly important to determine the true efficacy of any analgesic. Therefore it is surprising that despite the widespread use and support of paracetamol in OA until now there have been only four placebo controlled trials of this drug in OA. The first two studies reported in 19834 and in 19955 both demonstrated the superiority of paracetamol over placebo for pain relief in large joint OA using parallel group designs. However, the first study contained only 25 patients with knee OA followed up for just 6 weeks.4 The second study was larger (60 patients) but was of just 1 week’s duration and contained a mixed population with knee or hip OA.5 A third parallel group study was reported in 2003.6 This compared paracetamol, diclofenac, and placebo over a 12 week period in 82 patients with knee OA but was the first negative study for paracetamol, showing no difference between paracetamol and placebo using Western Ontario McMaster Osteoarthritis Index (WOMAC) assessments. Most recently, Pincus et al carried out a crossover study …

Objectives: Efforts to educate men about the controversy surrounding prostate cancer screening are well intended but rarely evaluated rigorously. We evaluated an evidence-based (EB) booklet for men designed to promote informed decision-making. We also determined whether men's preference for involvement in decision-making ("passive", "collaborative" or "active") modified its impact. Setting and methods: Men aged 40-70 years were recruited from the practices of 13 local general practitioners (GPs) in Sydney, Australia. They completed a self-administered questionnaire before seeing their GP, who, according to pre-randomised codes, distributed either our EB booklet or conventional information. Post-test questionnaires were mailed to men three days later. Of the 248 eligible men recruited, 214 (86% response rate) returned post-test questionnaires. Knowledge of evidence and of risk of developing and dying from prostate cancer, attitudes, interest in screening for prostate-specific antigen (PSA), worry and decisional conflict were the main outcome measures. Results: Compared with those receiving conventional information, men receiving the EB booklet had significantly improved knowledge (50% of items correct, 95% CI 46-53%; vs 45% correct, 95% CI 42-48%) (p=0.048) and lower levels of decisional conflict (mean 21.6, 95% CI 20.7-22.5; vs mean 24.3, 95% CI 23.4-25.2) (p Conclusions: Our findings show the benefits of providing evidence-based information to men about PSA screening. Our EB booklet facilitated informed choice, even among "passive" decision-makers.

Context Blood pressure control ( Objective To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings. Design The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002. Setting A total of 623 centers in the United States, Canada, and the Caribbean. Participants A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor. Interventions Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control ( Main outcome measures The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control ( Results Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants. Conclusions These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure

This second article in the series on pragmatic trials describes the challenges in selection of sites for pragmatic clinical trials and the impact on validity, precision, and generalizability of the results. The selection of sites is an important factor for the successful execution of a pragmatic trial and impacts the extent to which the results are applicable to future patients in clinical practice. The first step is to define usual care and understand the heterogeneity of sites, patient demographics, disease prevalence and country choice. Next, specific site characteristics are important to consider such as interest in the objectives of the trial, the level of research experience, availability of resources, and the expected number of eligible patients. It can be advisable to support the sites with implementing the trial-related activities and minimize the additional burden that the research imposes on routine clinical practice. Health care providers should be involved in an early phase of protocol development to generate engagement and ensure an appropriate selection of sites with patients who are representative of the future drug users.

Teenagers and young adults (TYA) cancer contributes substantially to morbidity and mortality in a population with muchto offer society. TYA place distinct challenges upon cancer care services, many reporting feeling marginalized and theirneeds not being met in adult or paediatric cancer services. Bone tumours such as osteosarcoma and Ewing sarcoma,because of theirage at presentation and the complexityof theircare, arewhere challenges in managing (TYA) with cancerhave often been most readily apparent. Bone sarcomas may be managed by paediatric or medical oncologists, andrequire fastidious attention to protocol. A lack of recent improvement in survival in TYAwith bone tumours may be linkedto a lack of specialist care, poor concordance with therapy in some situations and TYA-specific pharmacology.Participation in clinical trials, particularly of young adults, is low, hindering progress. All these requirements may be bestmet by a concerted effort to create collaborative care between adult and paediatric experts in bone sarcoma, workingtogether to meet TYA patients’ needs.Key words: osteosarcoma, bone tumours, Ewing sarcoma, teenage and young adults (TYA), adolescents and youngadults (AYA)

[Figure][1] Clinical trials begin with the design of the protocol. This involves expert clinicians, trialists, regulatory authorities, and sponsors gathering together to put forth their ideas on the basis of previous experience, results, and knowledge into the development of a rigorous design

Background The CONSORT Statement is a reporting guideline for authors when reporting randomized controlled trials (RCTs). It offers a standard way for authors to prepare RCT reports. It has been endorsed by many high-impact medical journals and by international editorial groups. This study was conducted to assess the endorsement of the CONSORT Statement by high-impact medical journals in China by reviewing their instructions for authors. Methodology/Principal Findings A total of 200 medical journals were selected according to the Chinese Science and Technology Journal Citation Reports, 195 of which publish clinical research papers. Their instructions for authors were reviewed and all texts mentioning the CONSORT Statement or CONSORT extension papers were extracted. Any mention of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URM) developed by the International Committee of Medical Journal Editors (ICMJE) or ‘clinical trial registration’ was also extracted. For journals endorsing the CONSORT Statement, their most recently published RCT reports were retrieved and evaluated to assess whether the journals have followed what the CONSORT Statement required. Out of the 195 medical journals publishing clinical research papers, only six (6/195, 3.08%) mentioned ‘CONSORT’ in their instructions for authors; out of the 200 medical journals surveyed, only 14 (14/200, 7.00%) mentioned ‘ICMJE’ or ‘URM’ in their instructions for authors, and another five journals stated in their instructions for authors that clinical trials should have trial registration numbers and that priority would be given to clinical trials which had been registered. Among the 62 RCT reports published in the six journals endorsing the CONSORT Statement, 20 (20/62, 32.26%) contained flow diagrams and only three (3/62, 4.84%) provided trial registration information. Conclusions/Significance Medical journals in China endorsing either the CONSORT Statement or the ICMJE's URM constituted a small percentage of the total; all of these journals used ambiguous language regarding what was expected of authors.

Background: Internationally, there is concern about the increased prescribing of pharmaceutical opioids for chronic non-cancer pain (CNCP). In part, this is related to limited knowledge about the long-term benefits and outcomes of opioid use for CNCP. There has also been increased injection of some pharmaceutical opioids by people who inject drugs, and for some patients, the development of problematic and/or dependent use. To date, much of the research on the use of pharmaceutical opioids among people with CNCP, have been clinical trials that have excluded patients with complex needs, and have been of limited duration (i.e. fewer than 12 weeks). The Pain and Opioids In Treatment (POINT) study is unique study that aims to: 1) examine patterns of opioid use in a cohort of patients prescribed opioids for CNCP; 2) examine demographic and clinical predictors of adverse events, including opioid abuse or dependence, medication diversion, other drug use, and overdose; and 3) identify factors predicting poor pain relief and other outcomes. Methods/Design: The POINT cohort comprises around 1,500 people across Australia prescribed pharmaceutical opioids for CNCP. Participants will be followed-up at four time points over a two year period. POINT will collect information on demographics, physical and medication use history, pain, mental health, drug and alcohol use, non-adherence, medication diversion, sleep, and quality of life. Data linkage will provide information on medications and services from Medicare (Australia’s national health care scheme). Data on those who receive opioid substitution therapy, and on mortality, will be linked. Discussion: This study will rigorously examine prescription opioid use among CNCP patients, and examine its relationship to important health outcomes. The extent to which opioids for chronic pain is associated with pain reduction, quality of life, mental and physical health, aberrant medication behavior and substance use disorders will be extensively examined. Improved understanding of the longer-term outcomes of chronic opioid therapy will direct community-based interventions and health policy in Australia and internationally. The results of this study will assist clinicians to better identify those patients who are at risk of adverse outcomes and who therefore require alternative treatment strategies.

Attention deficit/hyperactivity disorder (ADHD) is a common disorder and a plethora of new data has been published from clinical trials and national epidemiological databases in the last three years. In the United Kingdom Atomoxetine is currently the only licensed non-stimulant medication. As part of a systematic review of atomoxetine data Jan 2009-June 2011 formal searches found 750 citations. From these 13 met criteria for either review or systematic review papers and contained clinical data synthesis on atomoxetine. No individual review paper alone would be sufficient for clinicians to be updated at that time on all clinical aspects of atomoxetine data. The crucial data relating to clinical parity of atomoxetine and methylphenidate in trials and meta-analysis where relevant confounding biases are removed are not often discussed. Systematic review of complex data is critical for ADHD clinicians and will need regular updating due to the large volume of new data.