\u00a9 Purpose Trustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine's risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials. Methods We assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. Results Across data sources, the control was inconsistently reported as \u00e2 \u20ac placebo'-containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an \u00e2 \u20ac inactive' substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the \u00e2 \u20ac safety profile of (AAHS) is well characterised'. Conclusions The stated rationale of using AAHS control-to characterise the safety of the HPV virus-like particles-lacks clinical relevance. A non-placebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns. Trial registration numbers NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.
\n \n\n \n \nIntroduction: There is growing interest in the use of both proton beam therapy (PBT) and carbon ion radiation therapy (CIRT), which are types of hadrontherapy. Although neither are new technologies they have been subject to assessment by several Health Technology Assessment (HTA) agencies over the past years. The main claimed benefit of PBT and CIRT is a reduction in toxicity compared to conventional radiation therapy, resulting in fewer harms and a lower risk of induced secondary malignancies. Such an advantage would be particularly relevant to children and young adults. Sizeable hadrontherapy centres expansion is underway worldwide, while evidence supporting claims of superiority over conventional radiation therapy is thought to be currently insufficient. Objectives: The report is aimed at presenting the state of the art of clinical research in both PBT and CIRT, by summarising the evidence findings from most recent and uptodate HTA reports and by providing a description of all currently ongoing clinical studies. Methods: The search for HTA reports was carried out on 3 databases to identify reports published between January 2011 and June 2019. The quality of the identified reports was assessed using the AMSTAR instrument. The search for ongoing studies was carried out on four public registers in July 2019. All identified ongoing studies were included. Results: The overview of available evidence for PBT is drawn from five HTA reports on a total of 16 oncology indications, including 295 primary studies of any study design. One HTA report also included eight guidelines. All included HTA reports concluded that the quality of research is low and that there is insufficient evidence to support the claimed benefits of PBT. Seventytwo non-comparative ongoing studies and 25 comparative ongoing studies were identified. Seventeen were randomized controlled studies comparing Proton Beam Therapy with current practice. The search for HTA reports assessing the use of CIRT in oncology identified five reports, two of which were up to date and of good quality reporting data from primary studies. The largest report identified 56 studies on 13 indications, but only 27 studies (including only one randomised trial) could be included in a qualitative synthesis, providing no evidence of differences in efficacy and safety of CIRT compared to photontherapy. The other report focused on the effects of CIRT on chordomas and chondrosarcomas, highlighting the heterogeneity and inconsistency of available data mostly coming from low-quality studies. Thirtyseven ongoing studies were identified, 5 of which were RCT versus conventional treatment and 32 were single-arm studies. Table A summarises the findings, by clinical indication, from the included HTA reports and from the overview of ongoing clinical research. The Table reports the current level of certainty on superiority of PBT or CIRT compared to photon radiation therapy and the likelihood that future research results would resolve current uncertainty. Conclusions. Despite the growing number of studies being published and the growing number of PBT and/or CIRT centres opening or at a planning stage, there is persistent uncertainty on the added clinical benefit of hadrontherapy treatments over conventional radiation therapy. Clinical research currently underway may not contribute to solve this uncertainty. There is a lack of agreement on the appropriate study design to assess the effects of hadrontherapies and lack of coordination between centres in the production of joint research protocols to generate the necessary evidence. This has led to the production of numerous small, poorly designed and reported studies. These shortcomings might confine the use of PBT and CIRT to experimental treatments and require that patients willing to undergo PBT or CIRT be fully informed of the risks and uncertainties of the outcomes.
\n \n\n \n \nIn this chapter several application examples derived from the literature and from the real world show how new elementary mathematics like: Topological Weighted Centroid (TWC); Self Topological Weighted Centroid (STWC); Proximity Scalar Field; Gradient of the Scalar Field Relative Topological Weighted Centroid (TWCi); Paths from Arithmetic Centroid to entities; Paths between entities; Scalar Field of the trajectories, may help decision makers in situations characterized by limited amount of information, and how mathematics of complex system can improve the level of accuracy obtained with classical statistics. In particular the TWC proposes itself as a powerful method to identify the source of epidemic spread. The impressive results obtained in the example of Russian influenza spreading in Sweden in 1889 and in the colera spreading in London in 1854 are consistent with the idea that the spread of infectious disease is not random but follows a progression which is based on inherent but as yet undiscovered mathematical laws based on probabilistic density function. These methods, which require further for field evaluation and validation, could provide an additional powerful tool for the investigation of the early stages of an epidemic, and constitute the basis of new simulation methods to understand the process through which a disease is spread. \u00a9 2009 Bentham Science Publishers Ltd.
\n \n\n \n \nThis study evaluated the feasibility of using published data from more than one register to define the performance of different hip implants. In order to obtain estimates of performance for specific types of hip system from different register, we analysed data from the annual reports of five national and one Italian regional register. We extracted the number of implants and rates of implant survival at different periods of follow-up. Our aim was to assess whether estimates of cumulative survival rate were comparable with data from registers from different countries, and our conclusion was that such a comparison could only be performed incompletely. \u00a92009 British Editorial Society of Bone and Joint Surgery.
\n \n\n \n \nThis is the protocol for a review and there is no abstract. The objectives are as follows: To systematically review the evidence of effectiveness of interventions to interrupt or reduce the spread of respiratory viruses causing influenza-like illnesses (excluding vaccines and antivirals, which have already been covered by Cochrane Reviews) (Demicheli 2004; Jefferson 1999; Jefferson 2006b; Matheson 2003; Smith 2006; Swingler 2003). Copyright \u00a9 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
\n \n\n \n \nBackground. In an attempt to reduce the burden of influenza-like illness (ILI) on health resources, the Italian Ministry of Health released clinical practice guidelines (CPGs) on ILI management that include specific indications for the admission of children to the hospital. The aim of this study was to evaluate whether application of these CPGs reduced the rate of inappropriate hospital admissions. Methods. In the first phase, 2 independent observers recorded the number and clinical condition of children presenting with ILI to the emergency department (ED) of a large urban pediatric hospital and the main reasons for hospital admission. The latter were compared with the CPG indications for hospital admission to evaluate appropriateness. One year later (phase 2), we recorded the number of children with ILI admitted to the hospital by pediatricians trained in a 3-hour course on CPGs and by \"untrained\" control pediatricians. Results. In phase 1 of the study, 854 children accessed the ED; 318 (37.2%) had ILI. Of the latter, 26.2% were admitted to the hospital, and 33.7% of admissions were inappropriate according to CPG criteria. In phase 2, 16% of the children with ILI were admitted by CPG-trained pediatricians and 25.8% by control pediatricians. The number of inappropriate hospital admissions was higher among control than among CPG-trained pediatricians. Conclusions. ILI in children is associated with a high rate of inappropriate hospital admissions. Training of ED pediatricians in the application of a specific CPG may result in a substantial decrease of the admission rate and of inappropriate admissions. Copyright \u00a9 2005 by the American Academy of Pediatrics.
\n \n\n \n \n\u00a9 2017 American Medical Association. All rights reserved. IMPORTANCE: Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use \u201cnoninferiority\u201d hypotheses allowing a degree of inferior efficacy deemed \u201cclinically acceptable\u201d compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials. OBJECTIVE: To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of \u201cclinically acceptable\u201d inferiority. DESIGN AND SETTING: Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators. MAIN OUTCOMES AND MEASURES: Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose. RESULTS: We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy. CONCLUSIONS AND RELEVANCE: Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.
\n \n\n \n \nBackground: Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older. Methods: We searched five electronic databases to December, 2004, in any language, for randomised (n=5), cohort (n=49), and case-control (n=10) studies, assessing efficacy against influenza (reduction in laboratory-confirmed cases) or effectiveness against influenza-like illness (reduction in symptomatic cases). We expressed vaccine efficacy or effectiveness as a proportion, using the formula VE=1-relative risk (RR) or VE*=1-odds ratio (OR). We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications, and deaths. Findings: In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against influenza-like illness was 23% (95% CI 6-36) and non-significant against influenza (RR 1.04, 0.43-2.51). Well matched vaccines prevented pneumonia (VE 46%, 30-58) and hospital admission (VE 45%, 16-64) for and deaths from influenza or pneumonia (VE 42%, 17-59), and reduced all-cause mortality (VE 60%, 23-79). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19, 0.02-2.01), influenza-like illness (RR 1.05, 0.58-1.89), or pneumonia (RR 0.88, 0.64-1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%, 12-38) and all-cause mortality (VE 42%, 24-55). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%, 21-33), respiratory diseases (VE* 22%, 15-28), and cardiac disease (VE* 24%, 18-30), and for all-cause mortality (VE* 47%, 39-54). Interpretation: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest.
\n \n\n \n \nPeer review is well established across most academic disciplines, and publishers, editors, and researchers devote considerable resources to it. This paper uses examples from biomedical journals to examine its shortcomings. Although mainly anecdotal, the evidence suggests that peer review is sometimes ineffective at identifying important research and even less effective at detecting fraud. Most reviewers identify only the minority of a paper's defects and they may be biased. Peer review plus other editorial processes are associated with improvements in papers between submission and publication, but published papers remain hard to read and a significant proportion contain errors or omissions. While it is hard to quantify the costs, peer review does not seem an efficient use of resources. Research into the outcomes of peer review, the establishment of sound methods for measuring the quality of the process and its outcomes, and comparisons with alternative methods are needed.
\n \n\n \n \nThe publication of Unanticipated outcomes, the personal story of Jerome P. Kassirer, former editor-in-chief of the New England Journal of Medicine, gives the opportunity to consider the ethical principles of biomedical and scientific publishing. Conflict of interests, reporting, and fraud affect the credibility of medical communication, which rests on the robustness and transparency of its processes. Not all is yet lost, but we must be guided by strong moral principles and to a consistent framework of values.
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