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Many individuals with autism spectrum disorder (ASD) experience various degrees of impairment in social interaction and communication, restricted, repetitive behaviours, interests/activities. These impairments make a significant contribution to poorer everyday adaptive functioning. Yet, there are no pharmacological therapies to effectively treat the core symptoms of ASD. Since symptoms of ASD likely emerge from a complex interplay of vulnerabilities, environmental factors and compensatory mechanisms during the early developmental period, pharmacological interventions arguably would have the greatest impact to improve long-term outcomes when implemented at a young age. It is essential therefore, that clinical development programmes of investigational drugs in ASD include the paediatric population early on in clinical trials. Such trials need to offer the prospect of direct benefit (PDB) for participants. In most cases in drug development this prospect is supported by evidence of efficacy in adults. However, the effectiveness of treatment approaches may be age-dependent, so that clinical trials in adults may not provide sufficient evidence for a PDB in children. In this white paper, we consolidate recommendations from regulatory guidelines, as well as advice from the Food and Drug Administration, USA (FDA) and the Committee for Human Medicinal Products (CHMP) consultations on various development programmes on: 1) elements to support a PDB to participants in early paediatric clinical trials in ASD, including single-gene neurodevelopment disorders, 2) aspects of study design to allow for a PDB. This white paper is intended to be complementary to existing regulatory guidelines in guiding industry and academic sponsors in their conduct of early paediatric clinical trials in ASD. [ABSTRACT FROM AUTHOR]

Cognitive remediation is now widely recognized as an effective treatment for cognitive deficits in schizophrenia. Its effects are meaningful, durable, and related to improvements in everyday functional outcomes. As with many therapies, the evolution of cognitive remediation has resulted in treatment programs that use a variety of specific techniques, yet share common core principles. This paper is the product of a cognitive remediation expert working group consensus meeting to identify core features of the treatment and produce recommendations for its design, conduct, reporting, and implementation. Four techniques were identified as core features of cognitive remediation: facilitation by a therapist, cognitive exercise, procedures to develop problem-solving strategies, and procedures to facilitate transfer to real world functioning. Treatment techniques within each of these core features are presented to facilitate decisions for clinical trials and implementation in clinical settings. [ABSTRACT FROM AUTHOR]

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies. [ABSTRACT FROM AUTHOR]

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e. , different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis. [ABSTRACT FROM AUTHOR]

To describe current practice in the management of rectal cancer, to identify uncertainties that usually arise in the multidisciplinary team (MDT)'s discussions ('grey zones') and propose next generation studies which may provide answers to them. A questionnaire on the areas of controversy in managing T2, T3 and T4 rectal cancer was drawn up and distributed to the Rectal-Assisi Think Tank Meeting (ATTM) Expert European Board. Less than 70% agreement on a treatment option was indicated as uncertainty and selected as a 'grey zone'. Topics with large disagreement were selected by the task force group for discussion at the Rectal-ATTM. The controversial clinical issues that had been identified within cT2–cT3–cT4 needed further investigation. The discussions focused on the role of (1) neoadjuvant therapy and organ preservation on cT2-3a low-middle rectal cancer; (2) neoadjuvant therapy in cT3 low rectal cancer without high risk features; (3) total neoadjuvant therapy, radiotherapy boost and the best chemo-radiotherapy schedule in T4 tumors. A description of each area of investigation and trial proposals are reported. The meeting successfully identified 'grey zones' and, in the light of new evidence, proposed clinical trials for treatment of early, intermediate and advanced stage rectal cancer. [ABSTRACT FROM AUTHOR]

Abstract A new disposable microfluidic electrochemical paper-based device (ePAD) consisting of two spot sensors in the same working electrode for the simultaneous determination of uric acid and creatinine was developed. The spot 1 surface was modified with graphene quantum dots for direct uric acid oxidation and spot 2 surface modified with graphene quantum dots, creatininase and a ruthenium electrochemical mediator for creatinine oxidation. The ePAD was employed to construct an electrochemical sensor (based on square wave voltammetry analysis) for the simultaneous determination of uric acid and creatinine in the 0.010–3.0 µmol L−1 range. The device showed excellent analytical performance with a very low simultaneous detection limit of 8.4 nmol L−1 to uric acid and 3.7 nmol L−1 to creatinine and high selectivity. The ePAD was applied to the rapid and successful determination of those clinical biomarkers in human urine samples. Graphical abstract fx1 Highlights • An ePAD used for clinical biomarkers determination. • The ePAD consisting of two spot sensors in the same working electrode. • The spot 1 surface with graphene quantum dots for direct uric acid oxidation. • The spot 2 surface with GQDs, creatininase and an redox mediator for creatinine oxidation. • The ePAD showed high sensitivity for simultaneous determination of biomarkers. [ABSTRACT FROM AUTHOR]

Abstract Background Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. Aims To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. Sources A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. Content The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). Implications A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways. [ABSTRACT FROM AUTHOR]

Abstract: There is considerable empirical evidence that demonstrates that early intensive behavioral intervention (EIBI) produces substantial improvements in young children with autism. A central feature of this treatment approach is the reliance on continuous measurement of child performance during all treatment hours (20–40h per week) to ensure an objective and quantitative analysis of behavior. Pen-and-paper data collection is standard practice in service delivery agencies. An alternative is to collect data via an electronic format, however little research has been done on electronic data collection in these settings. The purpose of this study was to compare mTrial®, a program that allows therapists to record, store, and report discrete trial and other behavior data for students on a personal data assistant, to traditional pen-and-paper data, in terms of the accuracy of data collected and the time required to do it. Results suggest that both formats are of approximately equal accuracy but that traditional data collection is faster. Implications of the two data collection methods for data storage and analysis are also discussed. [Copyright &y& Elsevier]

The measurement of proglucagon-derived peptides (PGDPs) is a challenging task mainly due to major overlaps in their molecular sequence in addition to their low circulating levels. Here, we present the technical characteristics of novel ELISA assays measuring C-peptide and all six PGDPs including, for the first time, major proglucagon fragment (MPGF), and we validate them by performing a pilot in vivo cross-over randomized clinical trial on whether coffee consumption may affect levels of circulating PGDPs. The performance and technical characteristics of novel ELISA assays from Ansh measuring GLP-1, GLP-2, oxyntomodulin, glicentin, glucagon, MPGF and C-peptide were first evaluated in vitro in procured samples from a commercial vendor as well as in deidentified human samples from three previously performed clinical studies. Their performance was further evaluated in vivo in the context of a cross-over randomized controlled trial, in which 33 subjects consumed in random order and together with a standardized meal, 200 ml of either (a) instant coffee with 3 mg/kg caffeine, or (b) instant coffee with 6 mg/kg caffeine, (c) or water. All assays demonstrated high accuracy (spike and recovery and average linearity recovery ±15%), precision (inter-assay CV ≤ 6.4%), specificity (no significant cross-reactivities) and they were sensitive in low concentrations. Measurements of glicentin in archived random human samples using the Ansh assay correlated strongly with the glicentin measurements of Mercodia assay (r = 0.968) and of GLP-1 modestly with Millipore GLP-1 assay (r = 0.440). Oxyntomodulin, glicentin and glucagon concentrations were 2–5 fold higher in plasma compared to serum and serum concentrations correlated modestly (for oxyntomodulin and glicentin) or poorly (for glucagon) with the plasma concentrations. The evaluated assays detected a postprandial increase of gut-secreted PGDPs (GLP-1, GLP-2, oxyntomodulin and glicentin) and a postprandial decrease of pancreas-secreted PGDPs (glucagon, MPGF) in response to consuming coffee in comparison to consuming water with breakfast (enter here composition of breakfast). Only coffee consumption at the high dose alter levels of gut-secreted PGDPs and both at low and high dose to lower levels of pancreas-secreted PGDPs compared to water consumption during breakfast. Accurate, precise and specific measurement of six PGDPs is possible with novel assays. A randomized controlled trial demonstrated in vivo utility of those assays and supports the notion that coffee may exert part of its beneficial effects on glucose homeostasis in the short term through the regulation of PGDPs. • Sequences of PGDPs are overlapping and their low circulating levels make their measurement difficult. • Novel assays can perform an accurate, precise, and specific measurement of PGDPs. • Regulation of glucose homeostasis by coffee may occur through altering circulating levels of PGDPs. [ABSTRACT FROM AUTHOR]

Purpose Gestational diabetes influences risk for future metabolic disease including type 2 diabetes. Hemoglobin A1c (HbA1c) measurement assesses hemoglobin A glycosylation, and could theoretically be used as a test to estimate gestational glucose exposure. HbA1c assay on dried blood spots (DBS) is needed before potential application to statewide newborn screening (NBS) population studies. The study aimed to establish a reliable method to measure HbA1c on NBS DBS specimens. De-identified blood was used to generate trials to evaluate stability of HbA1c in DBS, optimal elution time, and stability of eluted blood. Results Analysis of DBS stability HbA1c measurements from 3 to 6 days after collection overestimated HbA1c values by a bias factor between 0.83 and 0.87. Sixty minutes of elution time produced maximal reproducibility and minimal bias of results. Within assay standard deviation: 0.058; average bias: − 0.02%. Stability of eluted blood did not vary significantly between days 0–2 after DBS elution. Conclusions Measurement of HbA1c levels on DBS from human blood is feasible. Results suggest new method using DBS to measure HbA1c level with the following characteristics: optimal time for sample analysis 3–6 days after collection, elution time of 60 min and eluted blood analysis within 2 days of elution. Measurement of neonatal HbA1c could provide insight regarding the infant's in utero exposure to glucose. [ABSTRACT FROM AUTHOR]

Abstract Quality improvement of care for patients with head and neck cancer remains a constant objective for the multidisciplinary team of physicians managing these patients. The purpose of quality assurance (QA) for head and neck surgical oncology and surgical trials however differs. While QA for the general head and neck patient aims to improve global outcome through structural changes of health-care systems, QA for surgical trials pursues the goal to help providing meaningful results from a clinical trial through the definition of structure, process and outcome measures within the trial. Establishing a QA program for surgical trials is challenging largely due to the variation in the execution of surgical techniques. Within this article, we describe the surgical QA program, which was developed for the phase III European Organisation for Research and Treatment of Cancer (EORTC) 1420 study, a trial assessing swallowing function after transoral surgery compared with radiation therapy. We propose based on our experience to further develop surgical QA for surgical clinical trials by introducing two separate components, one adaptable and one non-adaptable. The adaptable is tailored to the scientific question and specific procedure; the non-adaptable consists of minimal structural requirements of the clinical unit to participate in surgical trials at EORTC as well as guidelines and incentives for protocol adherence based on our experience in EORTC 24954. Finally, we strongly believe that surgical QA designed for clinical trials may serve as a basis for the development of QA surgical guidelines in clinical practice. Highlights • Quality assurance (QA) programs for surgical trials are challenging. • We propose a QA framework consisting of an adaptable and a non-adaptable component. • The adaptable is tailored to the scientific question and specific procedure. • The non-adaptable consists of minimal structural requirements of the clinical unit. • Surgical QA within clinical trials may serve as the basis for guidelines in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Background: Prints of electrocardiograms (ECGs) are often sent to core laboratories, where they are scanned, converted to a digital format, and read on-screen. These ECGs may differ from the original ECG because of variability introduced by the printer, scanner, or digitization software. Methods: Digital ECGs were recorded in 50 volunteers simultaneously using electrocardiographs from 2 different manufacturers. QT and RR intervals were measured on-screen on the digitized ECGs. To study the contribution of individual steps in the digitization process, differences in RR interval between 2 prints each of 50 digital ECGs, 2 scanned files of 50 prints, 2 digitized files from 50 scanned files, and 2 readings of 50 digitized ECGs (intrareader variability) were analyzed. Results: Repeatability coefficient for RR interval measurement was 18.5 milliseconds for machine 1 and 21 milliseconds for machine 2. Contributions of the printer were 6.5 milliseconds for machine 1 and 9.0 milliseconds for machine 2, digitization process was 5.5 milliseconds, and reader variability was 8.0 milliseconds. Variability of the scanner was negligible. Conclusions: The printer and digitization process account for significant differences in interval measurements in digitized ECGs. [Copyright &y& Elsevier]

The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development. A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues. Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by > 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting. Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts. • Multiple potential EEG are parameters known and some already used. • EEG parameters must be selected to address a specific question. • Due to significant heterogeneity of seizure types, syndromes, the use of EEG will vary according to purpose. • Evidence is required to "validate" the utility of a specific measure to a specific question before use in a trial. [ABSTRACT FROM AUTHOR]

Background Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato . The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. Aim The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. Sources This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. Implications The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi . Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value. [ABSTRACT FROM AUTHOR]

Objectives: Patient-reported outcomes (PROs; self-report assessments) are increasingly important in evaluating medical care and treatment efficacy. Electronic administration of PROs via computer is becoming widespread. This article reviews the literature addressing whether computer-administered tests are equivalent to their paper-and-pencil forms. Methods: Meta-analysis was used to synthesize 65 studies that directly assessed the equivalence of computer versus paper versions of PROs used in clinical trials. A total of 46 unique studies, evaluating 278 scales, provided sufficient detail to allow quantitative analysis. Results: Among 233 direct comparisons, the average mean difference between modes averaged 0.2% of the scale range (e.g., 0.02 points on a 10-point scale), and 93% were within ±5% of the scale range. Among 207 correlation coefficients between paper and computer instruments (typically intraclass correlation coefficients), the average weighted correlation was 0.90; 94% of correlations were at least 0.75. Because the cross-mode correlation (paper vs. computer) is also a test–retest correlation, with potential variation because of retest, we compared it to the within-mode (paper vs. paper) test–retest correlation. In four comparisons that evaluated both, the average cross-mode paper-to-computer correlation was almost identical to the within-mode correlation for readministration of a paper measure (0.88 vs. 0.91). Conclusions: Extensive evidence indicates that paper- and computer-administered PROs are equivalent. [ABSTRACT FROM AUTHOR]

Paper diaries are commonly used in health care and clinical research to assess patient experiences. There is concern that patients do not comply with diary protocols, possibly invalidating the benefit of diary data. Compliance with paper diaries was examined with a paper diary and with an electronic diary that incorporated compliance-enhancing features. Participants were chronic pain patients and they were assigned to use either a paper diary instrumented to track diary use or an electronic diary that time-stamped entries. Participants were instructed to make three pain entries per day at predetermined times for 21 consecutive days. Primary outcome measures were reported vs actual compliance with paper diaries and actual compliance with paper diaries (defined by comparing the written times and the electronically-recorded times of diary use). Actual compliance was recorded by the electronic diary. Participants submitted diary cards corresponding to 90% of assigned times (±15 min). However, electronic records indicated that actual compliance was only 11%, indicating a high level of faked compliance. On 32% of all study days the paper diary binder was not opened, yet reported compliance for these days exceeded 90%. For the electronic diary, the actual compliance rate was 94%. In summary, participants with chronic pain enrolled in a study for research were not compliant with paper diaries but were compliant with an electronic diary with enhanced compliance features. The findings call into question the use of paper diaries and suggest that electronic diaries with compliance-enhancing features are a more effective way of collecting diary information. [Copyright &y& Elsevier]

Objective: The aim of this study was to compare the effects of medium light roast (MLR) and medium roast (MR) paper-filtered coffee on cardiovascular risk factors in healthy volunteers. Methods: This randomized crossover trial compared the effects of consuming three or four cups (150 mL) of MLR or MR coffee per day for 4 wk in 20 healthy volunteers. Plasma lipids, lipoprotein( a) (Lp[a]), total homocysteine, and endothelial dysfunction-related inflammation biomarkers, serum glycemic biomarkers, and blood pressure were measured at baseline and after each intervention. Results: Both roasts increased plasma total cholesterol, low-density lipoprotein-cholesterol, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentrations (10%, 12%, and 18% for MLR; 12%, 14%, and 14% for MR, respectively) (P < 0.05). MR also increased high-density lipoporteincholesterol concentration by 7% (P = 0.003). Plasma fibrinogen concentration increased 8% after MR intake (P = 0.01), and soluble E-selectin increased 12% after MLR intake (P = 0.02). No changes were observed for Lp(a), total homocysteine, glycemic biomarkers, and blood pressure. Conclusion: Moderate paper-filtered coffee consumption may have an undesirable effect on plasma cholesterol and inflammation biomarkers in healthy individuals regardless of its antioxidant content. [ABSTRACT FROM AUTHOR]

Abstract: Paper spray uses solvent electrospray to produce gas phase ions from samples deposited on paper or other porous media by applying a high voltage to the wet substrate. The method is amenable to the analysis of small and large molecules and is applied here to pharmaceuticals from dried blood spots, making it potentially useful for quantitation of drugs during clinical trials or for therapeutic drug monitoring in a hospital or clinic. Several topics related to the analytical characteristics of paper spray for analyzing drugs in dried blood spots are explored. (1) The effect of protein–drug interactions was studied by comparing the ratio of propranolol (PRN) and atenolol (ATN), two drugs with widely disparate protein binding properties, in water and in blood and by spiking a deuterated analog of PRN into blood already containing PRN and then allowing the blood to incubate for different lengths of time. In the first experiment, the ratio of PRN to ATN was the same in both water and blood. In the second experiment, the ratio of PRN and PRN d7 was the same regardless of how long the deuterated analog was allowed to equilibrate in the blood. These results suggest that protein binding does not affect analyte signal, and that paper spray therefore measures the total drug concentration in blood at least in this case. (2) Alternative methods for incorporation of the isotopically labeled internal standard (IS), which is needed for quantitative results when analyzing drugs in dried blood spots, were tested. Because it is often not feasible to add the standard to the liquid blood at the point of collection, the IS must be incorporated into the dried blood in some way. The IS PRN d7 was combined with dried blood spots containing PRN in three different ways: by pretreating the paper with an IS solution, by doping the IS into the spray solvent, and by adding an IS solution to a punched out section of a DBS. The variance of the method was less than 8% when the IS was added to the paper either before adding the blood or when adding it afterwards to the dried blood punch. The variance was 16% when the IS was added to the solvent eluent. In all cases, the recovery of PRN was lower than that of the IS. (3) Finally, matrix effects were assessed by measuring the signal obtained for PRN d7 in matrices ranging from neat solution, to blank blood, to blood containing 1μg/mL of PRN. A neat solution was found to give approximately 10 times higher signal than blood, indicating that suppression of ionization is occurring. The presence of a high concentration of PRN did not affect the response for PRN d7. [Copyright &y& Elsevier]

As a result of an increasing life expectancy, the incidence of cancer cases diagnosed in the older population is rising. Indeed, cancer incidence is 11-fold higher in persons over the age of 65 than in younger ones. Despite this high incidence of cancer in older patients, solid data regarding the most appropriate approach and best treatment for older cancer patients are still lacking, mostly due to under-representation of these patients in prospective clinical trials. The clinical behaviour of common malignant diseases, e.g. breast, ovarian and lung cancers, lymphomas and acute leukaemias, may be different in older patients because of intrinsic variation of the neoplastic cells and the ability of the tumour host to support neoplastic growth. The decision to treat or not these patients should be based on patients’ functional age rather than the chronological age. Assessment of patients’ functional age includes the evaluation of health, functional status, nutrition, cognition and the psychosocial and economic context. The purpose of this paper is to focus on the influence of age on cancer presentation and cancer management in older cancer patients and to provide suggestions on clinical trial development and methodology in this population. [Copyright &y& Elsevier]

Summary: Over the past 10 years, quality of life (QOL) has been increasingly recognised as an important outcome parameter in head and neck cancer. Validated questionnaires have emerged and there has been an increase in the number of papers published each year. The aim of this article is to review the literature over the past five years (2000–2005 inclusive), to identify papers reporting outcomes using patient self-competed questionnaires and group these into themes. The tabulated summary allows for the areas of health related quality of life research to be identified and to explore issues that are perhaps deficit in the literature. The three authors independently searched the literature published in the English language using the ISI search engine with cross-reference using Pub Med and Ovid. The search terms were; quality of life, questionnaire, and head and neck cancer. Studies were placed in to one of five themes. There were 165 studies identified. The numbers in each theme were predictors of QOL [Hassanein KA, Musgrove BT, Bradbury E. Functional status of patients with oral cancer and its relation to style of coping, social support and psychological status. Br J Oral Maxillofac Surg 2001;39:340–5.], functional outcome [Klug C, Neuburg J, Glaser C, Schwarz B, Kermer C, Millesi W. Quality of life 2–10 years after combined treatment for advanced oral and oropharyngeal cancer. Int J Oral Maxillofac Surg 2002;31:664–9.], questionnaire development [Hanna E, Sherman A, Cash D, Adams D, Vural E, Fan CY, et al. Quality of life for patients following total laryngectomy vs chemoradiation for laryngeal preservation. Arch Otolaryngol Head Neck Surg 2004;130:875–9.], randomised clinical trials [Kanatas AN, Rogers SN. A national survey of health-related quality of life questionnaires in head and neck oncology. Ann R Coll Surg Engl 2004;86:6–10.], and reviews [Kanatas AN, Rogers SN. A national survey of health-related quality of life questionnaires in head and neck oncology. Ann R Coll Surg Engl 2004;86:6–10.]. Although many facets of HRQOL following head and neck cancer have been explored over the last five years the paper identifies issues where research is still lacking. [Copyright &y& Elsevier]

Abstract: Background: Patients may be asked to register a symptom daily in clinical trials. A problem associated with this kind of registration is that patients do not always fill in the diary at the appropriate time. As there is evidence showing that memory is unreliable, this undermines the entire purpose of collecting daily data on paper diaries. We aimed to compare accuracy, autocorrelations of consecutive entries, and responsiveness in paper diaries (P-Diaries) with electronic diaries (E-Diaries) and telephone diaries (T-Diaries). Methods: In a multi-centre, open, and parallel trial, 177 patients were allocated at random to P-Diaries, E-Diaries, or T-Diaries for the registration of symptoms through 4 weeks of treatment of gastro-oesophageal reflux disease (GORD). The primary outcome measure was the diaries. Findings: The proportion of patients completing all morning and all evening entries on time was low for both E-Diary and T-Diary groups. By accepting entries that were done half a day late, the proportion was increased to 19/57 (33%) for the E-Diary group, and to 9/61 (15%) for the T-Diary group. For P-Diary, where no control for time registration and entries was adapted, 37/59 (63%) of the patients completed all morning and all evening entries. A significant higher autocorrelation in P-Diaries was also found. Responsiveness was similar regardless of method of data capture. Interpretation: The results are consistent with the suggestion that data in the P-Diaries are not filled in at the appropriate time. Use of E-Diaries or T-Diaries improves quality and is recommended in future clinical trials. [Copyright &y& Elsevier]

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers. [ABSTRACT FROM AUTHOR]

Abstract: This review identifies a timeline to nanomedicine anticancer drug approval using the business model of inventors, innovators and imitators. By evaluating the publication record of nanomedicine cancer therapeutics we identified a trend of very few publications prior to FDA approval. We first enumerated the publications related to cancer involving polymers, liposomes or monoclonal antibodies and determined the number of citations per publication as well as the number of published clinical trials among the publications. Combining these data with the development of specific nanomedicines, we are able to identify an invention phase consisting of seminal papers in basic science necessary for the development of a specific nanomedicine. The innovation phase includes the first report, the development and the clinical trials involving that nanomedicine. Finally, the imitation phase begins after approval when others ride the wave of success by using the same formulation for new drugs or using the same drug to validate other nanomedicines. We then focused our analysis on nanomedicines containing camptothecin derivatives, which are not yet approved including two polymers considered innovations and one liposomal formulation in the imitation phase. The conclusion that may be drawn from the analysis of the camptothecins is that approved drugs reformulated in polymeric and liposomal cancer nanomedicines have a more difficult time navigating through the approval process than the parent molecule. This is probably due to the fact that for most currently approved drugs, reformulating them in a nanocarrier provides a small increase in performance that large pharmaceutical companies do not consider being worth the time, effort and expense of development. It also appears that drug carriers have a more difficult path through the clinic than monoclonal antibodies. The added complexity of nanocarriers also deters their use to deliver new molecular entities. Thus, the new drug candidates that might be most improved by drug delivery in nanocarriers are not formulated in this fashion. [Copyright &y& Elsevier]

Abstract: Coffee is among the most frequently consumed beverages worldwide and epidemiological studies indicate that its consumption is inversely related to the incidence of diseases in which reactive oxygen species (ROS) are involved (liver cirrhosis, certain forms of cancer and neurodegenerative disorders). It has been postulated that antioxidant properties of coffee may account for this phenomenon. To find out if consumption of paper filtered coffee which is the most widely consumed form in Central Europe and the US protects humans against oxidative DNA-damage, a controlled intervention trial with a cross-over design was conducted in which the participants (n =38) consumed 800ml coffee or water daily over 5 days. DNA-damage was measured in peripheral lymphocytes in single cell gel electrophoresis assays. The extent of DNA-migration attributable to formation of oxidised purines (formamidopyrimidine glycosylase sensitive sites) was decreased after coffee intake by 12.3% (p =0.006). Biochemical parameters of the redox status (malondialdehyde, 3-nitrotyrosine and the total antioxidant levels in plasma, glutathione concentrations in blood, intracellular ROS levels and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes) were not markedly altered at the end of the trial, also the urinary 8-isoprostaglandine F2α concentrations were not affected. Overall, the results indicate that coffee consumption prevents endogenous formation of oxidative DNA-damage in human, this observation may be causally related to beneficial health effects of coffee seen in earlier studies. [ABSTRACT FROM AUTHOR]

Abstract: An alternative to clinical trial paper-based data collection (PDC) is internet based electronic data collection (EDC), where the investigators over the internet enter data directly in the electronic database by themselves. In our study we considered clinical trial as a business process. Our objective was to model PDC and EDC process and to estimate the difference of the costs of PDC and EDC process for a sample clinical trial based on these models. We used Extended Event-driven Process Chains (eEPC) modeling technique to model PDC and EDC process. In order to evaluate the costs of the processes we assigned costs functions to each process function which appears in the model. The parameters which appear in these functions include efforts, staff prices and data quality parameters. We estimated the values of all these parameters and performed costs calculations for a sample clinical trial. Through an analysis and modeling efforts we identified sub-processes which contain main differences affecting duration and costs of the PDC and EDC process: data gathering at the research center; monitoring; and data management. The most significant model difference between PDC and EDC process appeared in data management sub-process. For the sample clinical trial considered in our simulation study and our parameters estimations the EDC process decreased data collection costs for 55%. For different scenarios of parameters variations we show that the EDC process may bring from 49% to 62% of savings when compared to PDC process. [Copyright &y& Elsevier]

A lack of recent improvement in survival in teenagers and young adults (TYA) with bone tumours may be linked to a lack of trial recruitment and specialist care, poor concordance with therapy, and/or TYA-specific pharmacology. To overcome these challenges, working together to create collaborative care between adult and paediatric experts in bone sarcoma is neccessary, to meet TYA patients' needs.Teenagers and young adults (TYA) cancer contributes substantially to morbidity and mortality in a population with much to offer society. TYA place distinct challenges upon cancer care services, many reporting feeling marginalized and their needs not being met in adult or paediatric cancer services. Bone tumours such as osteosarcoma and Ewing sarcoma, because of their age at presentation and the complexity of their care, are where challenges in managing (TYA) with cancer have often been most readily apparent. Bone sarcomas may be managed by paediatric or medical oncologists, and require fastidious attention to protocol. A lack of recent improvement in survival in TYA with bone tumours may be linked to 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 best met by a concerted effort to create collaborative care between adult and paediatric experts in bone sarcoma, working together to meet TYA patients' needs. [ABSTRACT FROM AUTHOR]

The optimal approach to desmoid-type fibromatosis has not been established as of today.Considering the unpredictable behaviour and the heterogeneity of this disease, we propose a treatment algorithm, based on a front-line wait and see (WS) approach and subsequent therapy in case of progression.A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis. [ABSTRACT FROM PUBLISHER]

• A simple and affordable protocol to fabricate μPADs was proposed based on the use of a 3D pen. • Hydrophobic barriers were effectively created with an acrylate-based resin. • The barriers revealed good chemical resistance when exposed to organic solvents. • The reported protocol allows the creation of zones with 2 mm diameter and channels with 3 mm width. • Clinical and environmental applications were successfully reported. This paper describes for the first time the use of a 3D pen to fabricate paper-based analytical devices. 3D pens are usually commercialized as "toy for children" and a kit containing four units and a handheld flashlight can be found at cost of US$ 10−15. The protocol involves the 3D pen drawing of the desirable layout on paper using an acrylic resin followed by a curing stage through a handheld flashlight. The barriers created with 3D pen revealed good chemical resistance when exposed to acid and alkaline solutions, surfactants and organic solvents, except ethanol. The proposed approach enabled the creation of zones with 2 mm diameter and channels with 3 mm wide. The analytical feasibility of the devices created with 3D pen was investigated through colorimetric measurements of clinically and environmentally relevant analytes using a free application for image capture and analysis. Considering the instrumental simplicity and the satisfactory analytical performance, we believe the reported approach exhibits potentiality to be implemented in laboratories or research centers with limited resources, opening possibilities to create the desirable devices for the point-of-need applications using only a pen and a flashlight. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcomes (PROs) are the consequences of disease and/or its treatment as reported by the patient. The importance of PRO measures in clinical trials for new drugs, biological agents, and devices was underscored by the release of the US Food and Drug Administration's draft guidance for industry titled “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.” The intent of the guidance was to describe how the FDA will evaluate the appropriateness and adequacy of PRO measures used as effectiveness end points in clinical trials... [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the measurement equivalence of individual response scale types by using a patient reported outcome measure (PROM) collected on paper and migrated into electronic format for use on the subject's own mobile device (BYOD) and on a provisioned device (site device).Methods: Subjects suffering from chronic health conditions causing daily pain or discomfort were invited to participate in this single-site, single visit, three-way crossover study. Association between individual item and instrument subscale scores was assessed by using the intraclass correlation coefficient (ICC) and its CI. Participant attitudes toward the use of BYOD in a clinical trial were assessed through use of a questionnaire.Results: In this study, 155 subjects (females 83 [54%]; males 72 [46%]) ages 19 to 69 years (mean ± SD: 48.6 ± 13.1) were recruited. High association between the modes of administration (paper, BYOD, site device) was shown with analysis of ICCs (0.79-0.98) for each response scale type, including visual analogue scale, numeric rating scale, verbal response scale, and Likert scale. Of the subjects, 94% (146 of 155) stated that they would definitely or probably be willing to download an app onto their own mobile device for a forthcoming clinical trial. Forty-five percent of subjects felt BYOD would be more convenient compared with 15% preferring a provisioned device (40% had no preference).Conclusions: This study provides strong evidence supporting the use of BYOD for PROM collection in terms of the conservation of instrument measurement equivalence across the most widely used response scale types, and high patient acceptance of the approach. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials require sufficient samples recruited within limited time and budget constraints. Trials with minors are additionally burdened by the requirement for youth assent and parental permission. This paper details the use of Facebook ads and traditional paper mailings to enroll 797 adolescent girls for a longitudinal, web-based, drug abuse prevention trial. Data on sample representativeness and retention are also provided.Methods: Facebook ads appeared on the pages of females aged 13 or 14years who reside in the U.S. Ads linked girls to a recruitment website. Girls who wanted more information submitted contact information and were mailed information packets to their homes containing, among other things, youth assent and parent permission forms. Returned forms were verified for accuracy and validity.Results: The Facebook ad campaign reached 2,267,848 girls and had a unique click-through rate of 3.0%. The campaign cost $41,202.37 with an average cost of $51.70 per enrolled girl. Information packets were mailed to 1,873 girls. Approximately one-half of girls returned the forms, and 797 girls were enrolled. The Facebook campaign's success varied by ad type, month, and day of the week. Baseline data revealed comparability to national data on demographic and substance use variables.Conclusions: Results suggest that Facebook ads provide a useful initial point of access to unparalleled numbers of adolescents. Clinical trials may benefit from a two-fold recruitment strategy that uses online ads to attract interested adolescents followed by traditional recruitment methods to communicate detailed information to adolescents and parents. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of font size and paper thickness on the response to, and completion of, a self-completion postal questionnaire among older people with joint pain.Study Design and Setting: Randomized trial. People aged 50 years and older with joint pain who consulted a general practitioner at one of five general practices in Central Cheshire were sent a postal questionnaire. Questionnaire format (large or small font size, thick or thin paper) was randomly allocated using a 2 x 2 factorial design.Results: Questionnaires were received from 502 out of 650 participants (crude response 77%). Response was significantly higher for participants receiving questionnaires with a larger font size (79.3% vs. 75.2%; hazard ratio 1.26, 95% confidence interval: 1.02, 1.56). Paper thickness had no significant effect on response. Completion (measure by assessing double-page turnover error) was increased in participants receiving questionnaires printed on thicker paper (3.2% vs. 7.1%; P=0.049) but was not affected by font size.Conclusion: This study demonstrates that questionnaires in larger font and on thicker paper may produce higher and more complete responses than surveys using standard size font and standard thickness paper, and should therefore be considered in studies among older people. [ABSTRACT FROM AUTHOR]

The most appropriate primary outcome measure for reproductive medicine has been discussed frequently. In 2003 the European Society for Human Reproduction and Embryology recommended that the outcome measure of assisted reproductive technology (ART) and non-ART should be singleton live birth. Although live birth is indeed the aim of clinical practice, and there is no discussion that it should be reported in infertility trials, we hereby provide arguments that plead for using ongoing pregnancy as the primary outcome in such trials. We feel that ongoing pregnancy best serves the many purposes of a primary outcome and best reflects the effectiveness of a treatment. [Copyright &y& Elsevier]

The quality of the very early emotional experiences in a child's life are recognized today as foundational in the mental health of becoming an adult. Unsurprisingly, clinicians and health authorities agree on the importance of early detection and treatment of any mental health issues experienced by the preschool child. This is even more important and challenging as young children do not yet have the language skills necessary to express their distress. But do the caregivers in charge of these populations have the best tools at their disposal to carry out that important mission in an efficient and scientifically robust manner reflecting the latest research findings and scientific literature? This is the question we try to answer in this paper. We revisited the theoretical underpinnings behind the concept of mentalization as playing a key role in the ability to understand the other's inner reality. We then carried out an extensive review of scientific papers written over the past 30 years on the subject. We examined mental representations of the adult on the child and analyzed those mentalizations as key inputs. We focused on extracting cross analyses of the mentalizations of one child by several adults with different functions in the life of the child. In this process, we used the PRISMA methodology applied to large international medical databases. We found that the qualitative approach, usually associated with a lengthy process, has been overwhelmingly used in trying to assess patients' mental states and to analyze the mentalizations on the patient, adult or child. Furthermore, cross analyses of mentalizations from more than one adult on a given child were almost nonexistent, despite having high epistemic and clinical potential. There is a dearth of reliable quantitative tools, able to capture and analyze the mentalizations on a patient, that are scientifically robust, transposable, and easy to implement in a clinical setting. The absence of such tools for medical professionals in charge of assessing preschool children contributes, in our view, the low detection and poor treatment of mental disorders in that particularly vulnerable population. We believe there is here an urgent unmet need and that such tools should be designed, validated, and deployed into the target populations as early as possible. [ABSTRACT FROM AUTHOR]

Objective: The journal received a request to retract a paper reporting the results of a triple-blind randomized placebo-controlled trial. The present and immmediate past editors expand on the journal's decision not to retract this paper in spite of undisputable evidence of scientific misconduct on behalf of one of the investigators.Methods: The editors present an ethical reflection on the request to retract this randomized clinical trial with consideration of relevant guidelines from the Committee on Publication Ethics (COPE) and the International Committee of Medical Journal Editors (ICMJE) applied to the unique contextual issues of this case.Results: In this case, scientific misconduct by a blinded provider of a homeopathy intervention attempted to undermine the study blind. As part of the study, the integrity of the study blind was assessed. Neither participants nor homeopaths were able to identify whether the participant was assigned to homeopathic medicine or placebo. Central to the decision not to retract the paper was the fact that the rigorous scientific design provided evidence that the outcome of the study was not affected by the misconduct. The misconduct itself was thought to be insufficient reason to retract the paper.Conclusion: Retracting a paper of which the outcome is still valid was in itself considered unethical, as it takes away the opportunity to benefit from its results, rendering the whole study useless. In such cases, scientific misconduct is better handled through other professional channels. [ABSTRACT FROM AUTHOR]

Past experience in science has thought us the importance of ethics in research. Research is important to the advancement of medicine and therefore good clinical practice in research maintains public trust which otherwise is not only lost but may cause science to seem negative. The rights of participants in the research trial are discussed. This includes knowledge and information about the research itself, the obligations of the researchers and the rights of participants during the research. The EU Directive on Good Clinical Practice in research trials is reviewed, including the twelve principles of the directive. The function and composition of Research Ethics Committees is discussed in the context of protecting patients and participants, asserting quality and monitoring of the research, qualifications of the scientists and liability. [ABSTRACT FROM AUTHOR]

Rotavirus is the leading cause of severe diarrhea in infants and young children. Live attenuated vaccines can lead to horizontal transmission with the risk of vaccine-derived disease in contacts. Transmission of pentavalent human-bovine reassortant rotavirus vaccine (RV5) strains leading to clinical disease was not well evaluated in the pivotal clinical trials, and only a few case reports have been described in the literature. We performed a systematic literature review to investigate secondary transmission of RV5 strains to unvaccinated subjects globally. We searched Embase, Medline for English papers, CNKI, Wan Fang for Chinese papers, and other resources (i.e., conference papers with full text) from January 2005 to June 2021. Eligibility criteria for inclusion were original articles based on non-interventional studies (case-control studies, cohort studies, cross-sectional studies) using RV5 strain transmission as outcomes. Other study or publication types were excluded, such as pre-clinical studies, interventional studies and case reports. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used, and study quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and the JBI checklist for cross-sectional studies to assess the risk of bias. The search generated 2,089 articles in total. Seven articles met all inclusion criteria, including six cohort studies and one cross-sectional study. All studies underwent quality assessment and complied with the quality criteria of the NOS or JBI checklist, respectively. Overall, none of the seven studies identified RV5 vaccine-type transmission to an unvaccinated population, in either hospitals or nurseries under a close contact environment. One study reported that 1% of unvaccinated infants had gastrointestinal symptoms, but all symptoms were attributed to other clinical conditions. We found no evidence of horizontal transmission of RV5 strains to unvaccinated infants in a context of a limited amount and the descriptive nature of the identified studies. [ABSTRACT FROM AUTHOR]

Emergency contraception (EC) with 10 mg mifepristone can prevent pregnancy up to 5 days after a single act of unprotected intercourse. No methods have been shown to be effective when treatment is administered more than 5 days after a single unprotected act or after several unprotected acts. Therefore, we tested, among 699 Chinese women requesting EC and exposed to the risk of pregnancy described, the potential of 100 mg mifepristone followed 2 days later by 0.4 mg misoprostol orally, when administered in the luteal phase of the cycle. At the time of treatment urinary pregnancy test had to be negative. Despite treatment, 25 women (2.7%) became pregnant. Among women with treatment delayed more than 5 days, the pregnancy rate was related to the number of acts of intercourse before treatment, being 1.4% with one episode and increasing to 6.5% when the number of episodes was two or more (relative risk = 4.62, 95% CI: 1.06–20.18). Side effects within a week after treatment were mild, and most women (57.2%) had menstruation within 3 days as expected. An occasional treatment with mifepristone in combination with misoprostol could provide an option for preventing unwanted pregnancies in women who are late for EC. [Copyright &y& Elsevier]