Search

Purpose: This paper reports a systematic review and meta-analysis protocol that will be used to evaluate the efficacy and safety of pembrolizumab, alone or combined with bevacizumab and other therapies, in adult women with cervical carcinoma from stage IB2 onwards. Methods: The protocol follows PRISMA-P recommendations and was registered on PROSPERO (CRD42024531233). The search will be conducted without restrictions on language and year of publication in the following databases: Pubmed, Embase, Scopus, Web of Science, Cancerlit, The World Health Organization (WHO), International Clinical Trials Registry Platform (ICTRP) and Clinical Trials Registry Platform. Grey literature will be searched using the following sources: Clinicaltrials.gov, Google Scholar and Opengrey. Manual search will be carried out for the reference lists of eligible studies. The studies will be selected independently by two reviewers and all completed or ongoing randomized clinical trials that evaluated the efficacy and safety of pembrolizumab, used alone or combined with chemotherapy, radiotherapy, bevacizumab or surgery, in adult women diagnosed with cervical cancer, will be included. The data extraction will include population characteristics, type of treatment and main outcomes of studies. The methodological quality of the studies will be assessed using the Cochrane Risk of Bias 2.0. The certainty of the evidence will be rated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Conclusions: The findings will be presented in narrative summary tables and a quantitative synthesis will be conducted using the 'meta' package of R software, version 4.3.1. This future systematic review may contribute with quality evidence for clinical decision-making on the use of pembrolizumab in women with cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website. Objectives: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis. Methods: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy. Results: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The “signal” in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical. Conclusion: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias). [ABSTRACT FROM AUTHOR]

Background: Stroke survivors with aphasia want to improve their everyday talking (discourse). In current UK practice, 90% of speech and language therapists believe discourse assessment and treatment is part of their role but are hampered by barriers in resources, time and expertise. There is a clinical need for well-articulated discourse assessment and treatments. LUNA is a multi-level treatment targeting words, sentences and discourse macrostructure in personal stories that addresses this clinical need. Objectives: This study aimed to assess the feasibility and acceptability of LUNA trial procedures in a randomised waitlist-controlled trial; and to evaluate preliminary efficacy. Methods: This paper reports a phase II, waitlist-controlled, proof-of-concept feasibility trial. Participants with chronic aphasia (n = 28) were recruited from the community and randomised to an Immediate (n = 14) or Delayed (n = 14) group. LUNA treatment was delivered twice weekly for 10 weeks via the videoconferencing technology, Zoom. Feasibility was assessed in terms of participant recruitment and retention, adherence, missing data, and treatment fidelity. Preliminary treatment efficacy was assessed in terms of between group differences in outcome measures relating to discourse, language, and psychosocial state. Results: The remote LUNA trial was feasible: 85% of those eligible consented to the trial; trial retention was 86%; 87% of treatment sessions were delivered as scheduled, and 79% of participants completed 80%+ of the treatment programme; data was missing only for participants who withdrew; treatment fidelity was high at 92% adherence; and only one clinical outcome measure demonstrated ceiling effects. ANCOVA analysis of the clinical outcome measures revealed group differences with medium and large effect sizes, indicating, improvements in the production of words, sentences, discourse macrostructure, overall language functioning (WAB-R), and psychosocial state (VAMS) following LUNA treatment. For most outcomes measured, similar treatment benefits were suggested in a secondary, non-parametric analysis. Conclusions: Large-scale evaluation of the clinical efficacy and cost-effectiveness of LUNA is warranted and supported by these findings. Trial registration: Clinical trials registration: NCT05847023 (clinical trials.gov). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In the context of a randomized controlled trial (RCT) on HIV testing in the emergency department (ED) setting, we evaluated preferences for survey modality and data quality arising from each modality. Methods: Enrolled participants were offered the choice of answering a survey via audio computer assisted self-interview (ACASI) or pen and paper self-administered questionnaire (SAQ). We evaluated factors influencing choice of survey modality. We defined unusable data for a particular survey domain as answering fewer than 75% of the questions in the domain. We then compared ACASI and SAQ with respect to unusable data for domains that address sensitive topics. Results: Of 758 enrolled ED patients, 218 (29%) chose ACASI, 343 chose SAQ (45%) and 197 (26%) opted not to complete either. Results of the log-binomial regression indicated that older (RR = 1.08 per decade) and less educated participants (RR = 1.25) were more likely to choose SAQ over ACASI. ACASI yielded substantially less unusable data than SAQ. Conclusions: In the ED setting there may be a tradeoff between increased participation with SAQ versus better data quality with ACASI. Future studies of novel approaches to maximize the use of ACASI in the ED setting are needed. [ABSTRACT FROM AUTHOR]

Slow patient enrollment or failing to enroll the required number of patients is a disruptor of clinical trial timelines. To meet the planned trial recruitment, site selection strategies are used during clinical trial planning to identify research sites that are most likely to recruit a sufficiently high number of subjects within trial timelines. We developed a machine learning approach that outperforms baseline methods to rank research sites based on their expected recruitment in future studies. Indication level historical recruitment and real-world data are used in the machine learning approach to predict patient enrollment at site level. We define covariates based on published recruitment hypotheses and examine the effect of these covariates in predicting patient enrollment. We compare model performance of a linear and a non-linear machine learning model with common industry baselines that are constructed from historical recruitment data. Performance of the methodology is evaluated and reported for two disease indications, inflammatory bowel disease and multiple myeloma, both of which are actively being pursued in clinical development. We validate recruitment hypotheses by reviewing the covariates relationship with patient recruitment. For both indications, the non-linear model significantly outperforms the baselines and the linear model on the test set. In this paper, we present a machine learning approach to site selection that incorporates site-level recruitment and real-world patient data. The model ranks research sites by predicting the number of recruited patients and our results suggest that the model can improve site ranking compared to common industry baselines. [ABSTRACT FROM AUTHOR]

Background: Over 1.3 billion people, or 16% of the world's population, live with some form of disability. Recent studies have reported that people with disabilities (PwD) might not be receiving state-of-the-art treatment for cancer as their non-disabled peers; our objective was to systematically review this topic. Methods: A systematic review was undertaken to compare cancer outcomes and quality of cancer care between adults with and without disabilities (NIHR Prospero register ID number: CRD42022281506). A search of the literature was performed in July 2022 across five databases: EMBASE, Medline, Cochrane Library, Web of Science and CINAHL databases. Peer-reviewed quantitative research articles, published in English from 2000 to 2022, with interventional or observational study designs, comparing cancer outcomes between a sample of adult patients with disabilities and a sample without disabilities were included. Studies focused on cancer screening and not treatment were excluded, as well as editorials, commentaries, opinion papers, reviews, case reports, case series under 10 patients and conference abstracts. Studies were evaluated by one reviewer for risk of bias based on a set of criteria according to the SIGN 50 guidelines. A narrative synthesis was conducted according to the Cochrane SWiM guidelines, with tables summarizing study characteristics and outcomes. This research received no external funding. Results: Thirty-one studies were included in the systematic review. Compared to people without disabilities, PwD had worse cancer outcomes, in terms of poorer survival and higher overall and cancer-specific mortality. There was also evidence that PwD received poorer quality cancer care, including lower access to state-of-the-art care or curative-intent therapies, treatment delays, undertreatment or excessively invasive treatment, worse access to in-hospital services, less specialist healthcare utilization, less access to pain medications and inadequate end-of-life quality of care. Discussion: Limitations of this work include the exclusion of qualitative research, no assessment of publication bias, selection performed by only one reviewer, results from high-income countries only, no meta-analysis and a high risk of bias in 15% of included studies. In spite of these limitations, our results show that PwD often experience severe disparities in cancer care with less guideline-consistent care and higher mortality than people without disabilities. These findings raise urgent questions about how to ensure equitable care for PwD; in order to prevent avoidable morbidity and mortality, cancer care programs need to be evaluated and urgently improved, with specific training of clinical staff, more disability inclusive research, better communication and shared decision-making with patients and elimination of physical, social and cultural barriers. [ABSTRACT FROM AUTHOR]

Monitoring of clinical trials is critical to the protection of human subjects and the conduct of high-quality research. Even though the adoption of risk-based monitoring (RBM) has been suggested for many years, the RBM approach has been less widespread than expected. Centralized monitoring is one of the RMB pillars, together with remote-site monitoring visits, reduced Source Data Verification (SDV) and Source Document Reviews (SDR). The COVID-19 pandemic promoted disruptions in the conduction of clinical trials, as on-site monitoring visits were adjourned. In this context, the transition to RBM by all actors involved in clinical trials has been encouraged. In order to ensure the highest quality of data within a COVID-19 clinical trial, a centralized monitoring tool alongside Case Report Forms (CRFs) and synchronous automated routines were developed at the clinical research platform, Fiocruz, Brazilian Ministry of Health. This paper describes how these tools were developed, their features, advantages, and limitations. The software codes, and the CRFs are available at the Fiocruz Data Repository for Research—Arca Dados, reaffirming Fiocruz's commitment to Open Science practices. [ABSTRACT FROM AUTHOR]

Background: Healthcare services regularly receive patient feedback, most of which is positive. Empirical studies suggest that health services can use positive feedback to create patient benefit. Our aim was to map all available empirical evidence for how positive patient feedback creates change in healthcare settings. Methods: Empirical studies in English were systematically identified through database searches (ACM Digital Library, AMED, ASSIA, CINAHL, MEDLINE and PsycINFO), forwards and backwards citation, and expert consultation. We summarise the characteristics of included studies and the feedback they consider, present a thematic synthesis of qualitative findings, and provide narrative summaries of quantitative findings. Results: 68 papers were included, describing research conducted across six continents, with qualitative (n = 51), quantitative (n = 10), and mixed (n = 7) methods. Only two studies were interventional. The most common settings were hospitals (n = 27) and community healthcare (n = 19). The most common recipients were nurses (n = 29). Most outcomes described were desirable. These were categorised as (a) short-term emotional change for healthcare workers (including feeling motivated and improved psychological wellbeing); (b) work-home interactional change for healthcare workers (such as improved home-life relationships); (c) work-related change for healthcare workers (such as improved performance and staff retention). Some undesirable outcomes were described, including envy when not receiving positive feedback. The impact of feedback may be moderated by characteristics of particular healthcare roles, such as night shift workers having less interaction time with patients. Some factors moderating the change created by feedback are modifiable. Conclusion: Further interventional research is required to assess the effectiveness and cost-effectiveness of receiving positive feedback in creating specific forms of change such as increases in staff retention. Healthcare managers may wish to use positive feedback more regularly, and to address barriers to staff receiving feedback. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to introduce a research methodology for the assessment of the acceptability of a humanoid robot at home for children with cochlear implants (CI). The quality of audiology rehabilitation for cochlear implanted child administrated at the hospital with pluri-weekly sessions is a major prognostic factor in the outcome on communications abilities, but represents also a constraint for families related to the access to care that are more difficult. Further, home training with tools would balance the equitable distribution of care in the territory and promote the child's progress. The humanoid robot should allow an ecological approach to this complementary training. Before developing this approach, it is necessary to study the acceptability of the humanoid robot at home, both by cochlear implanted child and their families. Ten families were chosen to have a humanoid robot at home, to explore their acceptability of the humanoid robot Pepper. The study lasts for 1 month per participants (i.e. cochlear implemented children and parent). Participants were invited to use the robot at home as much as they want. The humanoid robot Pepper was able to communicate and proposed activities not related to rehabilitation. Once a week during the study, data were collected from participants (questionnaires and robot's logs) and the smooth running of the study was checked. Questionnaires are used to evaluate the acceptability of the robot by children and parents. User data from the robot's logs are used to quantify the time and the actual use of the robot over the period of the study. Results of the experimentation will be reported, once all 10 participants have completed their passation. The robot is anticipated to be used and accepted by children with cochlear implants and their families. Clinical trial registration: Clinical Trials ID: NCT04832373; https://clinicaltrials.gov/. [ABSTRACT FROM AUTHOR]

There are challenges associated with recruiting children to take part in randomised clinical trials and as a result, compared to adults, in many disease areas we are less certain about which treatments are most safe and effective. This can lead to weaker recommendations about which treatments to prescribe in practice. However, it may be possible to 'borrow strength' from adult evidence to improve our understanding of which treatments work best in children, and many different statistical methods are available to conduct these analyses. In this paper we discuss four Bayesian methods for extrapolating adult clinical trial evidence to children. Using an exemplar dataset, we compare the effect of their modelling assumptions on the estimated treatment effect and associated heterogeneity. These modelling assumptions range from adult evidence being completely generalisable to being completely unrelated to the children's evidence. We finally discuss the appropriateness of these modelling assumptions in the context of estimating treatment effect in children. [ABSTRACT FROM AUTHOR]

Introduction: The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children's mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection. Methodology: A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes. Results: The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries. Conclusion: Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months. [ABSTRACT FROM AUTHOR]

In this paper we calculate the variation of the estimated vaccine efficacy (VE) due to the time-dependent force of infection resulting from the difference between the moment the Clinical Trial (CT) begins and the peak in the outbreak intensity. Using a simple mathematical model we tested the hypothesis that the time difference between the moment the CT begins and the peak in the outbreak intensity determines substantially different values for VE. We exemplify the method with the case of the VE efficacy estimation for one of the vaccines against the new coronavirus SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The aim of a clinical trial is to compare placebo to one or more treatments. The within-subject design is known to be more efficient than the between-subject design. However, in some trials that implement a within-subject design it is not possible to evaluate the placebo and all treatments within each subject. The design then becomes an incomplete within-subject design. An important question is how many subjects should be allocated to each combination of placebo and treatments. This paper studies optimal allocations of subjects in trials with a placebo and two treatments under heterogenous costs and variances. Two optimality criteria that consider the placebo-treatment contrasts simultaneously are considered, and the design is derived under a budgetary constraint. More subjects are allocated to those combinations with higher variances and lower costs. The optimal allocation is compared to the uniform allocation, which allocates equal number of subjects to each placebo and treatment combination, and to the complete within-subject design, where placebo and all treatments are available in each subject. The methodology is illustrated on the basis of an example on consultation time in primary care. A Shiny app is available to facilitate use of the methodology. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of stroke sequelae among patients is as high as 70%–80%. Flexor spasm is the most common stroke sequela, presenting a heavy burden to the patients and their families. This study will evaluate the results of randomized controlled trials to determine the efficacy and safety of hand manipulation acupuncture for the treatment of upper limb motor dysfunction after stroke. Methods: Eight databases, including China National Knowledge Infrastructure, Chinese Scientific Journal Database, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PubMed, Wanfang Database, and Web of Science, will be searched using English and Chinese search strategies. In addition, manual retrieval of research papers, conference papers, ongoing experiments, and internal reports, among others, will supplement electronic retrieval. All eligible studies published on or before January 15, 2021 will be selected. To enhance the effectiveness of the study, only clinical randomized controlled trials related to the use of manual acupuncture for the treatment of upper limb motor dysfunction after stroke will be included. Analysis: The Fugl-Meyer upper extremity assessment will be the primary outcome measure, whereas the Wolf Motor Function Test, Modified Ashworth Scale, arm movement survey test table, and upper extremity freehand muscle strength assessment scores will be the secondary outcomes. Side effects and adverse events will be included as safety evaluations. To ensure the quality of the systematic evaluation, study selection, data extraction, and quality assessment will be independently performed by two authors, and a third author will resolve any disagreement. Ethics and dissemination: This systematic review will evaluate the efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke. Since all included data will be obtained from published articles, it does not require ethical approval and will be published in a peer-reviewed journal. INPLASY registration number: INPLASY202110071. [ABSTRACT FROM AUTHOR]

Introduction: Chordoma is formed from embryonic residues or ectopic chordae and locally aggressive or malignant tumors. We visually analyzed the research tendency and hotspot of chordoma. Methods: The bibliometric analysis was conducted from the Web of Science Core Collection database over the past two decades. The term and strategies were as follows: "TS = (chordoma) OR TS = (chordoblastoma) OR TS = (chordocarcinoma) OR TS = (chordoepithelioma) OR TS = (chordosarcoma) OR TS = (notochordoma). AND Language: English. AND Reference Type: Article OR Review". A total of 2,118 references were retrieved and used to make a visual analysis by VOSviewer 1.6.15. Results: The chordoma was on a steady rise and chordoma but remained the focus of scholars and organizations over the last two decades. The Chinese institutions and scholars lacked cooperation with their counterparts in other countries. The citations of documents and co-citation analysis of cited references suggested that M.L. McMaster, B.P. Walcott, P. Bergh, and S. Stacchiotti were leading researchers in this field of chordoma and their papers had been widely accepted and inspired recent researches. Keywords associated with recent chemotherapy, PD-1-related immunotherapy, and SMARCB1/integrase interactor 1 (INI1) in chordoma were a shortage of research and there may be more research ideas in the future by scholars. The research of chordoma will continue to be the hotspot. Conclusions: Thus, explaining the molecular mechanism and potential role of transcriptional inhibition and immunologic responses to SMARCB1/INI1-negative poorly differentiated chordoma will be available for preclinical experiments and clinical trials and lead to new therapeutic opportunities for chordoma patients. [ABSTRACT FROM AUTHOR]

In this paper, we propose a partial randomized response technique to collect reliable sensitive data for estimation of population proportion in ranked set sampling (RSS) scheme using auxiliary information. The idea is to increase confidence and (or) co-operation of the respondents by providing them the option of both 'direct' and 'randomized' response for the inquired sensitive question. This option is quite logical because perception of sensitive (insensitive) inquiry can vary among respondents. The properties of the proposed method are discussed and compared with existing randomized response techniques. Cost analysis is also carried out to prove supremacy of the suggested method. Finally, an application to clinical trial on AIDS is included. [ABSTRACT FROM AUTHOR]

Objectives: Qualitative studies nested within clinical trials can provide insight into the treatment experience, how this evolves over time and where improved supportive care is required. The purpose of this qualitative study is to describe the lived experiences of men with advanced prostate cancer participating in the TheraP trial; a randomised trial of 177Lu-PSMA-617 compared with cabazitaxel chemotherapy. Methods: Fifteen men with advanced prostate cancer were recruited from the TheraP clinical trial with interviews conducted at three timepoints during the trial. An interpretative phenomenological approach was used, and interviews analysed using thematic analysis. This research paper reports the results from the mid-point, conclusion and follow up interviews, focusing specifically on participants' experiences of trial participation. Results: Three themes were identified representing the lived experiences of men with advanced prostate cancer participating in the TheraP trial: (1) facing limited options; (2) anticipating outcomes and (3) coping with health changes. Conclusions: Men who enrol in clinical trial of anti-neoplastic treatments for prostate cancer need targeted psychological and supportive care that includes attention to unique aspects of the experience of having prostate cancer and being in a clinical trial. As part of their trial experience, men with advanced prostate cancer need to be regularly assessed for survivorship needs, fully informed, supported and referred to services for regular care and support across the trajectory of their disease. Trial registration: NCT03392428. Registered on 8 January 2018 (ANZUP1603). [ABSTRACT FROM AUTHOR]

Paracetamol (N-acetyl-p-aminophenol (APAP), also known as acetaminophen) is used to relieve mild to moderate pain and reduce fever. APAP is widely used during pregnancy as it is considered safe when used as directed by regulatory authorities. However, a significant amount of epidemiological and experimental research suggests that prenatal exposure potentially alters fetal development. In this paper, we summarize the potentially harmful adverse effects of APAP and the limitations of the current evidence. It highlights the urgent need for a clinical trial, and the aim of the presented qualitative pilot study on APAP use during pregnancy is the feasibility of a large-scale randomized controlled trial (RCT). In the qualitative study, we included 232 Danish women from three hospitals in the spring of 2021. After recognizing the pregnancy, 48% had taken any APAP, and 6% had taken it weekly or more than weekly. A total of 27% who had taken APAP in the first trimester of pregnancy (even rarely) would potentially participate in an RCT. In a potential clinical trial, the women would need to be included early in the 1st trimester as the suspected harmful effects of APAP lies within this early reproductive developmental window. A possible recruitment strategy was explored. These data suggest that the target population appears positive towards an RCT. As a negative attitude among users has been considered the major hindrance for such a study, we cannot see hindrances for performing an RCT. [ABSTRACT FROM AUTHOR]

Background: Chronic carriage of S. Typhi or S. Paratyphi is an important source of enteric fever transmission. Existing guidance and treatment options for this condition are limited. This systematic review aims to assess the evidence concerning the efficacy of different antimicrobials in treating enteric fever chronic carriage. Methods: We searched major bibliographic databases using relevant keywords between 1946 and September 2021. We included all interventional studies that included patients with confirmed enteric fever chronic carriage and deployed an antimicrobial that remains in clinical practice today. Case reports and case series of under 10 patients were excluded. Two reviewers screened abstracts, selected articles for final inclusion and quality-assessed the included studies for risk of bias. Extracted data was analysed, with pooling of data and eradication rates for each antimicrobial calculated. As only one randomised controlled trial was identified, no meta-analysis was performed. Results: Of the 593 papers identified by the initial search, a total of eight studies met the inclusion criteria and were included in the systematic review. Evidence was identified for the use of fluoroquinolones and amoxicillin/ampicillin in the treatment for enteric fever chronic carriage. Fluoroquinolones were superior to amoxicillin/ampicillin with 92% of patients achieving eradication after one antimicrobial course compared to 68% (p = 0.02). The quality of included studies was poor, and all were carried out before 1990. Conclusion: This review identified fluoroquinolones and amoxicillin/ampicillin as treatment options for enteric fever chronic carriage, with fluoroquinolones the more effective option. However, this evidence pre-dates rises in antimicrobial resistance in enteric fever and therefore the significance of these findings to today's practice is unclear. Further research is needed to investigate whether these antimicrobials remain appropriate treatment options or whether alternative interventions are more effective. [ABSTRACT FROM AUTHOR]

Historical clinical trial registry data can only be retrieved by manually accessing individual clinical trials through registry websites. This limits the feasibility, accuracy and reproducibility of certain kinds of research on clinical trial activity and presents challenges to the transparency of the enterprise of human research. This paper presents cthist, a novel, free and open source R package that enables automated scraping of clinical trial registry entry histories and returns structured data for analysis. Documentation of the implementation of the package cthist is provided, as well as 3 brief case studies with example code. [ABSTRACT FROM AUTHOR]

Physical inactivity has been identified as a leading risk factor for premature mortality globally, and adolescents, in particular, have low physical activity levels. Schools have been identified as a setting to tackle physical inactivity. Economic evidence of school-based physical activity programmes is limited, and the costs of these programmes are not always collected in full. This paper describes a micro-costing and cost-consequence analysis of the ‘Girls Active’ secondary school-based programme as part of a cluster randomised controlled trial (RCT). Micro-costing and cost-consequence analyses were conducted using bespoke cost diaries and questionnaires to collect programme delivery information. Outcomes for the cost-consequence analysis included health-related quality of life measured by the Child Health Utility-9D (CHU-9D), primary care General Practitioner (GP) and school-based (school nurse and school counsellor) service use as part of a cluster RCT of the ‘Girls Active’ programme. Overall, 1,752 secondary pupils were recruited and a complete case sample of 997 participants (Intervention n = 570, Control n = 427) was used for the cost-consequence analysis. The micro-costing analysis demonstrated that, depending upon how the programme was delivered, ‘Girls Active’ costs ranged from £1,054 (£2 per pupil, per school year) to £3,489 (£7 per pupil, per school year). The least costly option was to absorb ‘Girls Active’ strictly within curriculum hours. The analysis demonstrated no effect for the programme for the three main outcomes of interest (health-related quality of life, physical activity and service use).Micro-costing analyses demonstrated the costs of delivering the ‘Girls Active’ programme, addressing a gap in the United Kingdom (UK) literature regarding economic evidence from school-based physical activity programmes. This paper provides recommendations for those gathering cost and service use data in school settings to supplement validated and objective measures, furthering economic research in this field. Trial registration: -ISRCTN, . [ABSTRACT FROM AUTHOR]

Lower back pain is a major public health problem. Despite claims that lumbar belts change spinal posture due to applied pressure on the trunk, no mechanical model has yet been published to prove this treatment. This paper describes a first model for belt design, based on the one hand on the mechanical properties of the fabrics and the belt geometry, and on the other hand on the trunk geometrical and mechanical description. The model provides the estimation of the pressure applied to the trunk, and a unique indicator of the belt mechanical efficiency is proposed: pressure is integrated into a bending moment characterizing the belt delordosing action on the spine. A first in-silico clinical study of belt efficiency for 15 patients with 2 different belts was conducted. Results are very dependent on the body shape: in the case of high BMI patients, the belt effect is significantly decreased, and can be even inverted, increasing the lordosis. The belt stiffness proportionally increases the pressure applied to the trunk, but the influence of the design itself on the bending moment is clearly outlined. Moreover, the belt/trunk interaction, modeled as sticking contact and the specific way patients lock their belts, dramatically modifies the belt action. Finally, even if further developments and tests are still necessary, the model presented in this paper seems suitable for in-silico pre-clinical trials on real body shapes at a design stage. [ABSTRACT FROM AUTHOR]

Background: In order to make informed decisions about how best to support children and young people with disabilities, effective strategies that facilitate active and meaningful participation in school are required. Clinical factors, diagnosis or impairments somewhat helpful in determining what should be provided in interventions. However, clinical factors alone will not offer a clear view of how to support participation. It is helpful then to look at wider psychosocial and environmental factors. The aim of this review was to synthesise evidence of psychosocial and environmental factors associated with school participation of 4–12 year old children with disabilities to inform the development of participation-fostering interventions. Methods: A systematic search and synthesis using realist methods was conducted of published research. Papers had to include consideration of psychosocial and/or environment factors for school participation of children with disabilities. The review was completed in accordance with the Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) and Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Papers were identified via Boolean search of the electronic databases MEDLINE, CINAHL, PhycINFO and ERIC (January 2006-October 2018). Appraisal focussed on contributions in terms of whether the articles are appropriate for the review (relevance) and research quality (rigour). Data were analyzed using content and thematic analysis methods using a realist framework. A narrative synthesis of results was reported. Results and implications: We identified 1828 papers in the initial search. Seventy two papers were included in the final synthesis. Synthesis of findings led to three overarching mechanisms representing psychosocial factors for children (1) identity (2) competence and (3) experience of mind and body. Environmental aspects (context) compromised five interrelated areas: (1) structures and organization, (2) peers, (3) adults, (4) space and (5) objects. Our synthesis provides insights on how professionals may organize efforts to improve children’s participation. Consideration of these findings will help to proactively deal with suboptimal participation outcomes. Development of theoretically determined assessments and interventions for management of school participation are now required. [ABSTRACT FROM AUTHOR]

Introduction: Previous research has shown that statin adherence for the primary prevention of CVD is lower compared to secondary prevention populations. Therefore the aim of this systematic review was to review predictors of statin adherence for the primary prevention of CVD. Methods: A systematic search of papers published between Jan 1984 and May 2017 was conducted in PubMed, PsycINFO, EMbase and CINAHL databases. A study was eligible for inclusion if; 1) it was a study of the general population or of patients with familial hypercholesterolemia, hypertension, diabetes or arthritis; 2) statins were prescribed; 3) adherence was defined and measured as the extent to which patients followed their statin regimen during the period of prescription, and 4) it was an original trial or observational study (excluding case reports). A study was subsequently excluded if 1) results were not presented separately for primary prevention; 2) it was a trial of an intervention (for example patient education). Papers were reviewed by two researchers and consensus agreed with a third. A quality assessment (QA) tool was used to formally assess each included article. To evaluate the effect of predictors, data were quantitatively and qualitatively synthesised. Results: In total 19 studies met the inclusion criteria and nine were evaluated as high quality using the QA tool. The proportion of patients classed as “adherent” ranged from 17.8% to 79.2%. Potential predictors of statin adherence included traditional risk factors for CVD such as age, being male, diabetes and hypertension. Income associated with adherence more strongly in men than women, and highly educated men were more likely and highly educated women less likely to be adherent. Alcohol misuse and high BMI associated with non-adherence. There was no association between polypharmacy and statin adherence. The evidence base for the effect of other lifestyle factors and health beliefs on statin adherence was limited. Conclusion: Current evidence suggests that patients with more traditional risk factors for CVD are more likely to be adherent to statins. The implications for future research are discussed. [ABSTRACT FROM AUTHOR]

Quality circles or peer review groups, and similar structured small groups of 6–12 health care professionals meet regularly across Europe to reflect on and improve their standard practice. There is debate over their effectiveness in primary health care, especially over their potential to change practitioners’ behaviour. Despite their popularity, we could not identify broad surveys of the literature on quality circles in a primary care context. Our scoping review was intended to identify possible definitions of quality circles, their origins, and reported effectiveness in primary health care, and to identify gaps in our knowledge. We searched appropriate databases and included any relevant paper on quality circles published until December 2017. We then compared information we found in the articles to that we found in books and on websites. Our search returned 7824 citations, from which we identified 82 background papers and 58 papers about quality circles. We found that they originated in manufacturing industry and that many countries adopted them for primary health care to continuously improve medical education, professional development, and quality of care. Quality circles are not standardized and their techniques are complex. We identified 19 papers that described individual studies, one paper that summarized 3 studies, and 1 systematic review that suggested that quality circles can effectively change behaviour, though effect sizes varied, depending on topic and context. Studies also suggested participation may affirm self-esteem and increase professional confidence. Because reports of the effect of quality circles on behaviour are variable, we recommend theory-driven research approaches to analyse and improve the effectiveness of this complex intervention. [ABSTRACT FROM AUTHOR]

The aim of the present clinical trial is to evaluate the efficacy of kinesio taping on patients with chronic low back pain, when the exploration identifies skin/fascia mobilization as a factor that could modify the treatment effect. This study is a randomized controlled trial with intention-to-treat analysis. Sixty-two participants with chronic low back pain were therefore recruited from a tertiary referral hospital. Targeted kinesio taping, according to skin/fascia mobility exploration, was applied in the experimental group (17 female/13 male; 49.47 ± 11.15 years) once a week for four sessions. The control group (17 female/14 male; 48.87 ± 9.09 years) underwent a placebo taping application. At post-treatment time there was a statistically significant reduction both in disability (Roland-Morris Disability Questionnaire) and pain (Numeric Pain Rating Scale) in the experimental group (disability: −2.88, 95% confidence interval [CI] −4.56 to −1.21, P <.001; pain: −1.58, 95% CI −2.67 to −0.54 P =.001) and the control group (disability: −1.82, 95% CI −3.46 to −0.17 P =.025; pain: −1.30, 95% CI −2.32 to −0.28 P =.008). However, at six months, these changes only remained significant in the experimental group (disability: −2.95, 95% CI −4.72 to −1.18, P <.001; pain: −1.06, 95% CI −2.07 to −0.04, P <.05). As a conclusion, the application of targeted kinesio taping produced a significant reduction in pain and disability, at 4 weeks and at 6 moths follow-up, although there were no differences between groups at any measurement time point. [ABSTRACT FROM AUTHOR]

A number of publishers and funders, including PLOS, have recently adopted policies requiring researchers to share the data underlying their results and publications. Such policies help increase the reproducibility of the published literature, as well as make a larger body of data available for reuse and re-analysis. In this study, we evaluate the extent to which authors have complied with this policy by analyzing Data Availability Statements from 47,593 papers published in PLOS ONE between March 2014 (when the policy went into effect) and May 2016. Our analysis shows that compliance with the policy has increased, with a significant decline over time in papers that did not include a Data Availability Statement. However, only about 20% of statements indicate that data are deposited in a repository, which the PLOS policy states is the preferred method. More commonly, authors state that their data are in the paper itself or in the supplemental information, though it is unclear whether these data meet the level of sharing required in the PLOS policy. These findings suggest that additional review of Data Availability Statements or more stringent policies may be needed to increase data sharing. [ABSTRACT FROM AUTHOR]

The concept of coherence was proposed for single-agent phase I clinical trials to describe the property that a design never escalates the dose when the most recently treated patient has toxicity and never de-escalates the dose when the most recently treated patient has no toxicity. It provides a useful theoretical tool for investigating the properties of phase I trial designs. In this paper, we generalize the concept of coherence to drug combination trials, which are substantially different and more challenging than single-agent trials. For example, in the dose-combination matrix, each dose has up to 8 neighboring doses as candidates for dose escalation and de-escalation, and the toxicity orders of these doses are only partially known. We derive sufficient conditions for a model-based drug combination trial design to be coherent. Our results are more general and relaxed than the existing results and are applicable to both single-agent and drug combination trials. We illustrate the application of our theoretical results with a number of drug combination dose-finding designs in the literature. [ABSTRACT FROM AUTHOR]

Background: Effective risk communication is challenging. Ensuring potential trial participants' understand 'risk' information presented to them is a key aspect of the informed consent process within clinical trials, yet minimal research has looked specifically at how to communicate probabilities to support decisions about trial participation. This study reports a systematic review of the literature focusing on presentation of probabilistic information or understanding of risk by potential trial participants. Methods: A search strategy for risk communication in clinical trials was designed and informed by systematic reviews of risk communication in treatment and screening contexts and supplemented with trial participation terms. Extracted data included study characteristics and the main interventions/findings of each study. Explanatory studies that investigated the methods for presenting probabilistic information within participant information leaflets for a clinical trial were included, as were interventions that focused on optimising understanding of probabilistic information within the context of a clinical trial. Results: The search strategy identified a total of 4931 studies. Nineteen papers were selected for full text screening, and seven studies included. All reported results from risk communication studies that aimed to support potential trial participants' decision making set within hypothetical trials. Five of these were randomised comparisons of risk communication interventions, and two were prospectively designed, non-randomised studies. Study interventions focused on probability presentation, risk framing and risk interpretation with a wide variety of interventions being evaluated and considerable heterogeneity in terms of outcomes assessed. Studies show conflicting findings when it comes to how best to present information, although numerical, particularly frequency formats and some visual aids appear to have promise. Conclusions: The evidence base surrounding risk communication in clinical trials indicates that there is as yet no clear optimal method for improving participant understanding, or clear consensus on how it affects their willingness to participate. Further research into risk communication within trials is needed to help illuminate the mechanisms underlying risk perception and understanding and provide appropriate ways to present and communicate risk in a trial context so as to further promote informed choices about participation. A key focus for future research should be to investigate the potential for learning in the evidence on risk communication from treatment and screening decisions when applied to decisions about trial participation. [ABSTRACT FROM AUTHOR]

Introduction: Research on research is key to enhancing efficacy in trial methodology. Clinical trials involving women during pregnancy and childbirth are limited, with a paucity of data guiding evidence-based practice. Following a prioritisation exercise that highlighted the top-ten unanswered recruitment questions, this qualitative evidence synthesis was designed specifically to focus on the barriers and enablers for clinicians/healthcare professionals in helping conduct randomised trials within the context of recruitment during pregnancy and childbirth. Methods: The synthesis was undertaken using Thomas and Harden's three stage thematic synthesis method and reported following the ENTREQ guidelines. Using a pre-determined SPIDER strategy, we conducted a comprehensive search of databases; Pubmed, CINAHL, PsycINFO, EMBASE, and grey searches for records until January 2019. We included all reports of qualitative data on recruiter's experiences, perceptions, views of recruiting women during pregnancy and childbirth to clinical trials. Altogether 13,401 records were screened, resulting in 31 full-text reviews, of which five were eligible for inclusion. Quality was appraised using CASP. Data were extracted onto a specifically defined form. We used thematic synthesis to identify descriptive and analytical themes, and to interpret and generate theory. Confidence was assessed using GRADE-CERQual. The review protocol is publicly available (OSF https://osf.io/g4dt9/). Results: Five papers (representing four individual studies) from two different countries were included. All studies focused on the experiences of trial recruiters in the maternity setting. We identified four analytical themes; Recruitment through a clinician's lens, Recruiters judgement on acceptability, From protocol to recruiters lived experience, Framing recruitment in context. These were linked by an overarching theme combining beliefs and power. Conclusion: The overarching theme combining beliefs and power links the experiences and perceptions of recruiters. This synthesis shows a gap between the trial design study protocol and the recruiter's lived experience. Strategies such as collaborative trial design, mitigating gatekeeping behaviours, and training may support recruiters in their endeavour. [ABSTRACT FROM AUTHOR]

Background: Disorganised attachment patterns in infants have been linked to later psychopathology. Services have variable practices for identifying and providing interventions for families of children with disorganised attachment patterns, which is the attachment pattern leading to most future psychopathology. Several recent government reports have highlighted the need for better parenting interventions in at risk groups. Objectives: The objective of this review and meta-analysis was to evaluate the clinical effectiveness of available parenting interventions for families of children at high risk of developing, or already showing, a disorganised pattern of attachment. Methods: Population: Studies were included if they involved parents or caregivers of young children with a mean age under 13 years who had a disorganised classification of attachment or were identified as at high risk of developing such problems. Included interventions were aimed at parents or caregivers (e.g. foster carers) seeking to improve attachment. Comparators included an alternative intervention, an attention control, treatment as usual or no intervention. The primary outcome was a disorganised pattern in childhood measured using a validated attachment instrument. Studies that did not use a true Randomised Controlled Trial (RCT) design were excluded from the review. Both published and unpublished papers were included, there were no restrictions on years since publication and foreign language papers were included where translation services could be accessed within necessary timescales. Results: A comprehensive search of relevant databases yielded 15,298 papers. This paper reports a systematic review as part of an NIHR HTA study identifying studies pre-2012, updated to include all papers to October 2016. Two independent reviewers undertook two stage screening and data extraction of the included studies at all stages. A Cochrane quality assessment was carried out to assess the risk of bias. In total, fourteen studies were included in the review. In a meta-analysis of these fourteen studies the interventions saw less disorganised attachment at outcome compared to the control (OR = 0.50, (0.32, 0.77), p = 0.008). The majority of the interventions targeted maternal sensitivity. We carried out exploratory analyses to examine factors that may influence treatment outcome but these should be treated with caution given that we were limited by small numbers of studies. Conclusions: Parenting interventions that target parental sensitivity show promise in reducing disorganised attachment. This is limited by few high quality studies and the fact that most studies are with mothers. More high quality randomised controlled trials are required to elucidate this further. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a chronic disease commonly managed by family physicians, with the most prevalent complication being cardiovascular disease (CVD). Clinical practice guidelines have been developed to support clinicians in the care of diabetic patients. We conducted a pragmatic cluster randomized controlled trial (RCT) of a printed educational toolkit aimed at improving CVD management in diabetes in primary care, and found no effect, and indeed, the possibility of some harm. We conducted a qualitative evaluation to study the strategy for guideline implementation employed in this trial, and to understand its effects. This paper focuses solely on the qualitative findings, as the RCT’s quantitative results have already been reported elsewhere. Methods and Findings: All family practices in the province of Ontario had been randomized to receive the educational toolkit by mail, in either the summer of 2009 (intervention arm) or the spring of 2010 (control arm).A subset of 80 family physicians (representing approximately 10% of the practices randomized and approached, with records on 1,592 randomly selected patients with diabetes at high risk for CVD) then took part in a chart audit and reflective feedback exercise related to their own practice in comparison to the guideline recommendations. They were asked to complete two forms (one pre- and one post-audit) in order to understand their awareness of the guidelines pre-trial, their expectations regarding their individual performance pre-audit, and their reflections on their audit results. In addition, individual interviews with thirteen other family physicians were conducted. Textual data from interview transcripts and written commentary from the pre- and post-audit forms underwent qualitative descriptive analysis to identify common themes and patterns. Analysis revealed four main themes: impressions of the toolkit, awareness was not the issue, ‘it’s not me it’s my patients’, and chart audit as a more effective intervention than the toolkit. Participants saw neither the toolkit content nor its dissemination strategy to be effective, indicating they perceived themselves to be aware of the guidelines pre-trial. However, their accounts also indicated that they may be struggling to prioritize CVD management in the midst of competing demands for their attention. Upon receiving their chart audit results, many participants expressed surprise that they had not performed better. They reported that the audit results would be an important motivator for behaviour change. Conclusions: The qualitative findings outlined in this paper offer important insights into why the intervention was not effective. They also demonstrate that physicians have unperceived needs relative to CVD management and that the chart audit served to identify shortcomings in their practice of which they had been hitherto unaware. The findings also indicate that new methods of intervention development and implementation should be explored. This is important given the high prevalence of diabetes worldwide; appropriate CVD management is critical to addressing the morbidity and mortality associated with the disease. [ABSTRACT FROM AUTHOR]

The development of a new drug is an extremely high-risk enterprise. The attrition rates of development projects and the average costs for each launched product are daunting, and the completion of a development program requires a very long time horizon. These facts imply that there are huge potential gains, should one be able to improve efficiency and enhance decision-making capabilities. In this paper, we argue that substantial gains can be achieved by adapting a holistic view of drug development. Historically, too much planning, design and decision-making in the pharmaceutical development has been based on locally optimising separate parts of the development program, and too often important sources of uncertainty are ignored. We propose instead a model-based approach built on two essential pillars; (1) an integrated holistic view of the development program, including post-launch marketing and sales, with all parts evaluated simultaneously; (2) an explicit appreciation of all relevant sources of uncertainty. Computer simulations are utilised to evaluate the properties of the program options at hand, and to provide valuable quantitative decision support. Applications of this modelling approach have proven to add large value to development projects in terms of better program options being generated and more value-adding decisions taken. [ABSTRACT FROM AUTHOR]

Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients. Traditionally, the observed events of patients are aggregated into means and subsequently analyzed using, for example, a repeated measures ANOVA. This procedure has drawbacks. One drawback is that these patient means have different standard errors, first, because the variance of the underlying events differs between patients and second, because the number of events per patient differs. In this paper, we argue that such data should be analyzed by applying a multilevel analysis using the individual observed events as separate nested observations. Such a multilevel approach handles this drawback and it also enables the examination of varying drug effects across patients by estimating random effects. We show how multilevel analyses can be applied to on-demand medication data from a clinical trial investigating the efficacy of a drug for women with low sexual desire. We also explore linear and quadratic time effects that can only be performed when the individual events are considered as separate observations and we discuss several important statistical topics relevant for multilevel modeling. Taken together, the use of a multilevel approach considering events as nested observations in these types of data is advocated as it is more valid and provides more information than other (traditional) methods. [ABSTRACT FROM AUTHOR]

Background: High quality dietary intake data is required to support evidence of diet-disease relationships exposed in clinical research. Source data verification may be a useful quality assurance method in this setting. The present pilot study aimed to apply source data verification to evaluate the quality of the data coding process for dietary intake in a clinical trial and to explore potential barriers to data quality in this setting. Methods: Using a sample of 20 cases from a clinical trial, source data verification was conducted between three sets of data derived documents: transcripts of audio-recorded diet history interviews, matched paper-based diet history forms and outputs from nutrition analysis software. The number of cases and rates of discrepancies between documents were calculated. A total of five in-depth interviews with dietitians collecting and coding dietary data were thematically analysed. Results: Some 2024 discrepancies were identified. The highest discrepancy rate was 57.49%, and occurred between diet history interviews and nutrition analysis software outputs. Sources of the discrepancies included both quantities and frequencies of food intake. The highest discrepancy rate was for the food group “vegetable products and dishes”. In-depth interviews implicated recall bias of trial participants as a cause of discrepancies, but dietitians also acknowledged a possible subconscious influence of having to code reported foods into nutrition analysis software programs. Conclusion: The accuracy of dietary intake data appeared to depend on the level of detailed food data required. More support for participants on reporting consumption, and incorporating supportive tools to guide estimates of food quantities may facilitate a more consistent coding process and improve data quality. This pilot study offers a novel method and an overview of dietary intake data coding measurement errors. These findings may warrant further investigation in a larger sample. [ABSTRACT FROM AUTHOR]

Background: The performance of a new diagnostic test is typically evaluated against a comparator which is assumed to correspond closely to some true state of interest. Judgments about the new test’s performance are based on the differences between the outputs of the test and comparator. It is commonly assumed that a small amount of uncertainty in the comparator’s classifications will negligibly affect the measured performance of a diagnostic test. Methods: Simulated datasets were generated to represent typical diagnostic scenarios. Comparator noise was introduced in the form of random misclassifications, and the effect on the apparent performance of the diagnostic test was determined. An actual dataset from a clinical trial on a new diagnostic test for sepsis was also analyzed. Results: We demonstrate that as little as 5% misclassification of patients by the comparator can be enough to statistically invalidate performance estimates such as sensitivity, specificity and area under the receiver operating characteristic curve, if this uncertainty is not measured and taken into account. This distortion effect is found to increase non-linearly with comparator uncertainty, under some common diagnostic scenarios. For clinical populations exhibiting high degrees of classification uncertainty, failure to measure and account for this effect will introduce significant risks of drawing false conclusions. The effect of classification uncertainty is magnified further for high performing tests that would otherwise reach near-perfection in diagnostic evaluation trials. A requirement of very high diagnostic performance for clinical adoption, such as a 99% sensitivity, can be rendered nearly unachievable even for a perfect test, if the comparator diagnosis contains even small amounts of uncertainty. This paper and an accompanying online simulation tool demonstrate the effect of classification uncertainty on the apparent performance of tests across a range of typical diagnostic scenarios. Both simulated and real datasets are used to show the degradation of apparent test performance as comparator uncertainty increases. Conclusions: Overall, a 5% or greater misclassification rate by the comparator can lead to significant underestimation of true test performance. An online simulation tool allows researchers to explore this effect using their own trial parameters () and the source code is freely available (). [ABSTRACT FROM AUTHOR]

Falls are commonly reported post-stroke. Ankle-foot orthoses (AFOs) are often provided to improve safety and walking, but the effect of their use in the reduction of falls after stroke is unknown. A randomized controlled trial (RCT) on the effects of AFO-provision after stroke was performed. Effects on clinical scales, 3D-gait kinematics and muscle-activity were previously reported. This paper aims to study the effects of AFO-provision on occurrence and circumstances of falls/near falls. The RCT included unilateral hemiparetic stroke patients. AFOs were provided either early (study week 1) or delayed (study week 9). Both groups were compared in the first eight weeks of the study and diaries were used to register falls/near falls and their circumstances. Follow-up measurements were performed in week 9–52, in which both groups were provided with AFOs. Functional Ambulation Categories and Berg Balance Scale were assessed to determine walking independence and balance, respectively. Last known scores were noted in case of an incident. Thirty-three subjects were included (16 early, 17 delayed). In week 1–8, the early group, who were provided with AFOs, fell significantly more frequently compared with the delayed group, 11 versus 4 times, respectively (Incidence Rate Ratio = 2.9, p = 0.039). Out of the falls recorded in the early group, 63.6% occurred without wearing AFOs. Most of these falls occurred during transfers (36.4%) and standing (27.3%), and notably it were the subjects who did not have independent walking ability. No differences were found for near falls in week 1–8, or for falls/near falls in week 9–52. Six severe consequences (including fractures) were reported from a fall. To conclude, the subjects provided with AFOs early after stroke reported a higher number of falls, compared to the subjects that had not yet been provided with AFOs. However, in the subjects provided with AFOs, 63.6% of the falls occurred whilst without wearing the AFO. Furthermore, the majority of these incidents took place whilst subjects had no independent walking ability. This raises an interesting question of the importance of careful instructions to patients and their relatives, and the influence of potential cognitive impairments on the ability of the subjects to take on these instructions. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled clinical trials require management effort, involving huge organizational, economic and informatics investments. Information technology offers opportunities to approach clinical trial methodology in new ways. However, there are only a few reports of computerized data and drug management systems. Objective: This paper describes a novel software created specifically for the management of a randomized trial of diet and metformin in people with metabolic syndrome (the Me.Me.Me. trial). Methods: Me.Me.Me. is an ongoing phase III randomized controlled trial in healthy people with metabolic syndrome to test the hypothesis that comprehensive lifestyle changes and/or metformin can prevent age-related chronic non-communicable diseases. To manage all the phases of the trial, we created a software which is a state pattern machine, user friendly, web-based, able to maintain the correct balance between randomization groups, and structured in various levels of security in order to guarantee the participant’s privacy and compliance with the study protocol. The software achieves budget savings: drug management is not based on patients’ packs, but on the actual need for drugs according to each participant’s “state”, with strict guidelines for the handling and supply of medication. Results: The trial is ongoing and recruitment will close on August 31, 2018. To date, 11737 bottles of metformin/placebo have been dispensed to 1054 randomized participants, with drug savings of 29.5%. Conclusions: A software which takes into account the “state” of participant might be a powerful resource for developing and managing clinical trials, helping avoid poor treatment allocation, and wastage of drugs and money. Me.Me.Me. trial: EUDRACT no. . ClinicalTrials.gov Identifier: . [ABSTRACT FROM AUTHOR]

Intravoxel incoherent motion (IVIM) imaging is a magnetic resonance imaging (MRI) technique widely used in clinical applications for various organs. However, IVIM imaging at low b-values is a persistent problem. This paper aims to investigate in a systematic and detailed manner how the number of low b-values influences the estimation of IVIM parameters. To this end, diffusion-weighted (DW) data with different low b-values were simulated to get insight into the distributions of subsequent IVIM parameters. Then, in vivo DW data with different numbers of low b-values and different number of excitations (NEX) were acquired. Finally, least-squares (LSQ) and Bayesian shrinkage prior (BSP) fitting methods were implemented to estimate IVIM parameters. The influence of the number of low b-values on IVIM parameters was analyzed in terms of relative error (RE) and structural similarity (SSIM). The results showed that the influence of the number of low b-values on IVIM parameters is variable. LSQ is more dependent on the number of low b-values than BSP, but the latter is more sensitive to noise. [ABSTRACT FROM AUTHOR]

Objectives: Little is known about the physician characteristics associated with appraisal skills of research evidence, especially the assessment of the validity of study methodology. This study aims to explore physician characteristics associated with proper assessment of overstated conclusions in research abstracts. Design: A secondary analysis of a randomized controlled trial. Setting and participants: We recruited 567 volunteers from the Japan Primary Care Association. Methods: Participants were randomly assigned to read the abstract of a research paper, with or without an overstatement, and to rate its validity. Our primary outcome was proper assessment of the validity of its conclusions. We investigated the association of physician characteristics and proper assessment using logistic regression models and evaluated the interaction between the associated characteristics and overstatement. Results: We found significant associations between proper assessment and post-graduate year (odds ratio [OR] = 0.67, 95% confidence interval [CI] 0.49 to 0.91, for every 10-year increase) and research experience as a primary investigator (PI; OR = 2.97, 95% CI 1.65 to 5.34). Post-graduate year and PI had significant interaction with overstatement (P = 0.015 and < 0.001, respectively). Among participants who read abstracts without an overstatement, post-graduate year was not associated with proper assessment (OR = 1.04, 95% CI 0.82 to 1.33), and PI experience was associated with lower scores of the validity (OR = 0.58, 95% CI 0.35 to 0.96). Conclusion: Physicians who have been in practice longer should be trained in distinguishing overstatements in abstract conclusions. Physicians with research experience might be informed that they tend to rate the validity of research lower regardless of the presence or absence of overstatements. Trial registration: . [ABSTRACT FROM AUTHOR]

Objectives: Although systematic evaluation has confirmed the efficacy of fresh fecal microbiota transplantation (FMT) for treatment of recurrent and/or refractory and/or relapse C. difficile infection (RCDI), it lacks the support of well-designed randomized controlled trials (RCTs), and the latest guidelines do not optimize the management of FMT. In this paper, we focus on an in-depth study of fresh FMT and fecal infusion times to guide clinical practice. Methods: We reviewed studies in PubMed, Medline, Embase, the Cochrane library and Cochrane Central written in English. The retrieval period was from the establishment of the databases to September 20th, 2018. The retrieval objects were published RCTs of RCDI treated by fresh FMT. The intervention group was fresh FMT group, while the control group included antibiotic therapy or placebo or frozen FMT or capsule. The primary and secondary outcomes were the clinical remission of diarrhea without relapse after 8–17 weeks and the occurrence of severe adverse events, respectively. Subgroup analysis analyzed the effect of single and multiple fecal infusions. Two authors independently completed the information extraction and assessed risk of bias and overall quality of the evidence. Results: 8 randomized controlled trials met the inclusion criteria, involving 537 patients (273 in the fresh FMT group and 264 in the control group). The recurrence rate of clinical diarrhea in the fresh FMT group was 11.0% (30/273), which was significantly lower than the control group (24.6%, 65/264; P < 0.05); the pooled relative risk (RR) was 0.38 (95%CI:0.16–0.87; I2 = 67%; P = 0.02) in the fresh FMT group, and the clinical heterogeneity was significant and random effects model was used; However, there was no significant difference neither for the effect of antibiotic treatment/frozen feces transplanted by enema (RR = 1.07; 95%CI: 0.64–1.80; I2 = 0%; P = 0.79) or capsule/frozen feces transplanted by colonoscopy (RR = 0.42; 95%CI: 0.05–3.94; I2 = 43%; P = 0.45) compared with fresh FMT. The subgroup analysis showed that FMT by multiple infusions could effectively and significantly (RR = 0.24; 95%CI:0.10–0.58; I2 = 0%; P = 0.001) improve the clinical diarrhea remission rate. Most mild to moderate adverse events caused by FMT were self-limited and could be quickly alleviated; no severe adverse events happened because of FMT. Conclusions: Overall, the use of fresh feces for bacterial transplantation was the best efficiency for RCDI compared to antibiotic therapy or placebo. The fecal transmission method by enema was not ideal, but capsules or frozen feces transported by colonoscopy could be an alternative treatment compared to fresh FMT. For patients with severe RCDI, multiple fecal transplants can effectively improve their diarrhea remission rate. The focus of future research should be on how to standardize the production of capsules or frozen feces to better guide the clinical management of RCDI patients by FMT. [ABSTRACT FROM AUTHOR]

Aim: We aimed to identify and evaluate the quality and evidence of the motor learning literature about intervention studies regarding the contextual interference (CI) effect (blocked vs. random practice order) in children with brain lesions and typically developing (TD) children. Method: Eight databases (Cinahl, Cochrane, Embase, PubMed, Pedro, PsycINFO, Scopus and Web of Knowledge) were searched systematically with predefined search terms. Controlled studies examining the CI effect in children (with brain lesions or TD) were included. Evidence level, conduct quality, and risk of bias were evaluated by two authors independently. A best evidence synthesis was performed. Results: Twenty-five papers evaluating TD children were included. One of these studies also assessed children with cerebral palsy. Evidence levels were I, II, or III. Conduct quality was low and the risk of bias high, due to methodological issues in the study designs or poor description thereof. Best evidence synthesis showed mainly no or conflicting evidence. Single tasks showed limited to moderate evidence supporting the CI effect in TD children. Conclusion: There is a severe limitation of good-quality evidence about the CI effect in children who practice different tasks in one session, especially in children with brain lesions. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. Methods: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio’s (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). Results: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). Conclusions: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to verify the efficacy of using theory-based strategies on implementation intentions in promoting physical activity (PA) among adults. Methods: This review was conducted in accordance with the PRISMA recommendations. The search was carried out in seven electronic databases (LILACS, PubMed, SciELO, Cochrane, Web of Science) and two searches of the “grey literature” were performed (Openthesis and OpenGrey). Randomized clinical trials (RCT), published up to September 2016, were considered eligible for this study. Two reviewers independently and systematically evaluated the eligibility criteria, and performed data extraction. A meta-analysis was performed for the purpose of comparing the effect between the intervention and control groups. The effect sizes were grouped in two subgroups with the purpose of more accurately verifying the effect caused by reinforcing the implementation intentions strategy, and using the inverse variance statistical method with random effects models to estimate the main effect of the implementation intention strategy on the PA behavior. Heterogeneity among the studies was evaluated by using I-square statistics, and the Jadad scale to evaluate the quality of included papers. Results: The search resulted in 12,147 records, of which 13 RCTs were considered eligible for this review. Sample age ranged from 18 to 76 years, and participants had conditions such as medullary lesion, coronary disease, obesity, diabetes mellitus, sedentarism or occupational stress. When the summary of the effect was analyzed in the meta-analysis, the result found in the subgroup with reinforcement of the implementation intentions strategy was 0.25 (IC 95% = 0.05–0.45) in favor of the intervention group. This demonstrated that application of the implementation intentions strategy was capable of increasing PA practice in the participants of these studies, in comparison with others that did not use this reinforcement. Conclusion: The findings of this review indicated that application of the theory of implementation intentions promoted PA behavior among the adults who received reinforcement of this strategy. The systematic review protocol was registered in the PROSPERO database under the number CRD42018090482. [ABSTRACT FROM AUTHOR]

Clinical trials are necessary in order to develop treatments for diseases; however, they can often be costly, time consuming, and demanding to the patients. This paper summarizes several common methods used for optimal design that can be used to address these issues. In addition, we introduce a novel method for optimizing experiment designs applied to HIV 2-LTR clinical trials. Our method employs Bayesian techniques to optimize the experiment outcome by maximizing the Expected Kullback-Leibler Divergence (EKLD) between the a priori knowledge of system parameters before the experiment and the a posteriori knowledge of the system parameters after the experiment. We show that our method is robust and performs equally well if not better than traditional optimal experiment design techniques. [ABSTRACT FROM AUTHOR]

EFs are a set of processes that supports many cognitive domains as goal setting, monitoring, planning, and cognitive-behavioural flexible control. Currently, many standardized paper-and-pencil tests or scales are used to assess EFs. These tests are easy to administer, score, and interpret but present some limitations in terms of generalizability of behaviours in real life. More recently, Information and Communication Technology has provided a higher ecological validity in the EFs assessment. In order to increase the ecological validity, we have developed a serious game (SG), named EXPANSE, which aim was to compare the participants’ game performance (latency times, and correct answers) with the results obtained in the traditional tasks and scales. 354 healthy subjects participated to the study and the findings showed significant correlations among standard tasks and the serious game. The exploratory nature of the present study, on one hand, highlighted that SG could be an additional behavioral tool to assess EFs and, on the other, we need further investigations, including clinical populations, for better defining the game sensitivity toward EF components. Finally, the results show that serious games are a promising technology for the evaluation of real cognitive behavior along with traditional evaluation. [ABSTRACT FROM AUTHOR]

Purpose: The CONSORT extension for patient reported outcomes (PROs) aims to improve reporting, but guidance on the optimal integration with clinical data is lacking. This study examines in detail the reporting of PROs and clinical data from randomized controlled trials (RCTs) in gastro-intestinal cancer to inform design and reporting of combined PRO and clinical data from trials to improve the ‘take home’ message for clinicians to use in practice. Materials and Methods: The case study was undertaken in gastro-intestinal cancer trials. Well-conducted RCTs reporting PROs with validated instruments were identified and categorized into those combining PRO and clinical data in a single paper, or those separating data into linked primary and supplemental papers. Qualitative methods were developed to examine reporting of the critical interpretation of the trial results (trial exegesis) in the papers in relation of the PRO and clinical outcomes and applied to each publication category. Results were used to inform recommendations for practice. Results: From 1917 screened abstracts, 49 high quality RCTs were identified reported in 36 combined and 15 linked primary and supplemental papers. In-depth analysis of manuscript text identified three categories for understanding trial exegesis: where authors reported a “detailed”, “general”, or absent PRO rationale and integrated interpretation of clinical and PRO results. A total of 11 (30%) and 6 (16%) combined papers reported “detailed” PRO rationale and integrated interpretation of results although only 2 (14%) and 1 (7%) primary papers achieved the same standard respectively. Supplemental papers provide better information with 11 (73%) and 3 (20%) achieving “detailed” rationale and integrated interpretation of results. Supplemental papers, however, were published a median of 20 months after the primary RCT data in lower impact factor journals (median 16.8 versus 5.2). Conclusion: It is recommended that single papers, with detailed PRO rationale and integrated PRO and clinical data are published to optimize trial exegesis. Further work to examine whether this improves the use of PRO data to inform practice is needed. [ABSTRACT FROM AUTHOR]

Introduction: Translational research is central to international health policy, research and funding initiatives. Despite increasing use of the term, the translation of basic science discoveries into clinical practice is not straightforward. This systematic search and narrative synthesis aimed to examine factors enabling or hindering translational research from the perspective of basic and clinician scientists, a key stakeholder group in translational research, and to draw policy-relevant implications for organisations seeking to optimise translational research opportunities. Methods and Results: We searched SCOPUS and Web of Science from inception until April 2015 for papers reporting scientists’ views of the factors they perceive as enabling or hindering the conduct of translational research. We screened 8,295 papers from electronic database searches and 20 papers from hand searches and citation tracking, identifying 26 studies of qualitative, quantitative or mixed method designs. We used a narrative synthesis approach and identified the following themes: 1) differing concepts of translational research 2) research processes as a barrier to translational research; 3) perceived cultural divide between research and clinical care; 4) interdisciplinary collaboration as enabling translation research, but dependent on the quality of prior and current social relationships; 5) translational research as entrepreneurial science. Across all five themes, factors enabling or hindering translational research were largely shaped by wider social, organisational, and structural factors. Conclusion: To optimise translational research, policy could consider refining translational research models to better reflect scientists’ experiences, fostering greater collaboration and buy in from all types of scientists. Organisations could foster cultural change, ensuring that organisational practices and systems keep pace with the change in knowledge production brought about by the translational research agenda. [ABSTRACT FROM AUTHOR]

Background: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. Objectives: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. Methods: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. Results: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. Conclusions and Implications: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. Systematic Review Protocol Number: CRD42015014145 [ABSTRACT FROM AUTHOR]