A survey of experts to identify methods to detect problematic studies: Stage 1 of the INSPECT-SR Project.

Background: Randomised controlled trials (RCTs) inform healthcare decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INSPECT-SR project is developing a tool to identify problematic RCTs in systematic reviews of healthcare-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion. Methods: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorised these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list. Results: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool. Conclusions: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Advanced Magnetic Resonance Imaging Biomarkers of the Injured Spinal Cord: A Comparative Study of Imaging and Histology in Human Traumatic Spinal Cord Injury.

A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.

Conflict of interest policies at Australian medical schools.

BACKGROUND: Pharmaceutical industry exposure is widespread during medical training and may affect education and clinical decision-making. Medical faculties' conflict of interest (COI) policies help to limit this exposure and protect students against commercial influence. AIMS: Our aim was to investigate the prevalence, content and strength of COI policies at Australian medical schools and changes since a previous assessment conducted in 2009. METHODS: We identified policies by searching medical school and host university websites in January 2021, and contacted deans to identify any missed policies. We applied a modified version of a scorecard developed in previous studies to examine the content of COI policies. All data were coded in duplicate. COI policies were rated on a scale from 0 (no policy) to 2 (strong policy) across 11 items per medical school. Oversight mechanisms and sanctions were also assessed, and current policies were compared with the 2009 study. RESULTS: Of 155 potentially relevant policies, 153 were university-wide and two were specific to medical schools. No policies covered sales representatives, on-site sponsored education or free samples. Oversight of consultancies had improved substantially, with 76% of schools requiring preapproval. Disclosure policies, while usually present, were weak, with no public disclosure required. CONCLUSION: We found little indication that Australian medical students are protected from commercial influence on medical education, and there has been limited COI policy development within the past decade. More attention is needed to ensure the independence of medical education in Australia.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

Magnetic Peripheral Nerve Stimulation (mPNS) for Chronic Pain.

Purpose: To assess magnetic peripheral nerve stimulation (mPNS) for the treatment of chronic or chronic and intractable neuropathic pain with a retrospective review case series. Patients and methods: Twenty-four patients with predominantly neuropathic post-traumatic or postoperative pain were treated as per protocol and followed for 3 months. Results: Data were analyzed as an observational, one-armed, convenience sample. Graphical evidence backed up by a mixed model for repeated measures statistical analysis showed a highly significant reduction of pain at one month out from initial treatment with mPNS. At one month, there was a 3.8 average reduction in pre-pain scores using a visual analogue scale (VAS), and that relief was generally durable measured out to three months. Two-thirds of patients, deemed responders, showed an 87% reduction in pain. Opioid reduction was seen in 58.3% of responders as well. Conclusion: mPNS appears promising for the treatment of chronic or chronic and intractable neuropathic pain for many of the same indications as traditional electrical peripheral nerve stimulation (PNS). No invasive techniques or implants are needed for mPNS.

Should low-risk DCIS lose the cancer label? An evidence review.

BACKGROUND: Population mammographic screening for breast cancer has led to large increases in the diagnosis and treatment of ductal carcinoma in situ (DCIS). Active surveillance has been proposed as a management strategy for low-risk DCIS to mitigate against potential overdiagnosis and overtreatment. However, clinicians and patients remain reluctant to choose active surveillance, even within a trial setting. Re-calibration of the diagnostic threshold for low-risk DCIS and/or use of a label that does not include the word 'cancer' might encourage the uptake of active surveillance and other conservative treatment options. We aimed to identify and collate relevant epidemiological evidence to inform further discussion on these ideas. METHODS: We searched PubMed and EMBASE databases for low-risk DCIS studies in four categories: (1) natural history; (2) subclinical cancer found at autopsy; (3) diagnostic reproducibility (two or more pathologist interpretations at a single time point); and (4) diagnostic drift (two or more pathologist interpretations at different time points). Where we identified a pre-existing systematic review, the search was restricted to studies published after the inclusion period of the review. Two authors screened records, extracted data, and performed risk of bias assessment. We undertook a narrative synthesis of the included evidence within each category. RESULTS: Natural History (n = 11): one systematic review and nine primary studies were included, but only five provided evidence on the prognosis of women with low-risk DCIS. These studies reported that women with low-risk DCIS had comparable outcomes whether or not they had surgery. The risk of invasive breast cancer in patients with low-risk DCIS ranged from 6.5% (7.5 years) to 10.8% (10 years). The risk of dying from breast cancer in patients with low-risk DCIS ranged from 1.2 to 2.2% (10 years). Subclinical cancer at autopsy (n = 1): one systematic review of 13 studies estimated the mean prevalence of subclinical in situ breast cancer to be 8.9%. Diagnostic reproducibility (n = 13): two systematic reviews and 11 primary studies found at most moderate agreement in differentiating low-grade DCIS from other diagnoses. Diagnostic drift: no studies found. CONCLUSION: Epidemiological evidence supports consideration of relabelling and/or recalibrating diagnostic thresholds for low-risk DCIS. Such diagnostic changes would need agreement on the definition of low-risk DCIS and improved diagnostic reproducibility.

Low-risk prostate lesions: An evidence review to inform discussion on losing the "cancer" label.

BACKGROUND: Active surveillance (AS) mitigates harms from overtreatment of low-risk prostate lesions. Recalibration of diagnostic thresholds to redefine which prostate lesions are considered "cancer" and/or adopting alternative diagnostic labels could increase AS uptake and continuation. METHODS: We searched PubMed and EMBASE to October 2021 for evidence on: (1) clinical outcomes of AS, (2) subclinical prostate cancer at autopsy, (3) reproducibility of histopathological diagnosis, and (4) diagnostic drift. Evidence is presented via narrative synthesis. RESULTS: AS: one systematic review (13 studies) of men undergoing AS found that prostate cancer-specific mortality was 0%-6% at 15 years. There was eventual termination of AS and conversion to treatment in 45%-66% of men. Four additional cohort studies reported very low rates of metastasis (0%-2.1%) and prostate cancer-specific mortality (0%-0.1%) over follow-up to 15 years. Overall, AS was terminated without medical indication in 1%-9% of men. Subclinical reservoir: 1 systematic review (29 studies) estimated that the subclinical cancer prevalence was 5% at <30 years, and increased nonlinearly to 59% by >79 years. Four additional autopsy studies (mean age: 54-72 years) reported prevalences of 12%-43%. Reproducibility: 1 recent well-conducted study found high reproducibility for low-risk prostate cancer diagnosis, but this was more variable in 7 other studies. Diagnostic drift: 4 studies provided consistent evidence of diagnostic drift, with the most recent (published 2020) reporting that 66% of cases were upgraded and 3% were downgraded when using contemporary diagnostic criteria compared to original diagnoses (1985-1995). CONCLUSIONS: Evidence collated may inform discussion of diagnostic changes for low-risk prostate lesions.

A new paradigm for investigating real-world social behavior and its neural underpinnings.

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study natural behavior for basic and clinical translational research. We describe an immersive social and behavioral paradigm implemented in patients undergoing evaluation for surgical treatment of epilepsy, with electrodes implanted in the brain to determine the source of their seizures. Our studies entail collecting eye tracking with other behavioral and psychophysiological measurements from patient-participants during unscripted behavior, including social interactions with clinical staff, friends, and family in the hospital room. This approach affords a unique opportunity to study the neurobiology of natural social behavior, though it requires carefully addressing distinct logistical, technical, and ethical challenges. Collecting neurophysiological data synchronized to behavioral and psychophysiological measures helps us to study the relationship between behavior and physiology. Combining across these rich data sources while participants eat, read, converse with friends and family, etc., enables clinical-translational research aimed at understanding the participants' disorders and clinician-patient interactions, as well as basic research into natural, real-world behavior. We discuss data acquisition, quality control, annotation, and analysis pipelines that are required for our studies. We also discuss the clinical, logistical, and ethical and privacy considerations critical to working in the hospital setting.

Branded Care: The Policy Implications of Pharmaceutical Industry-Funded Nursing Care Related to Specialty Medicines.

An increasing proportion of new drugs approved for market worldwide are now high cost, specialty medicines. Pharmaceutical marketers face the challenge of convincing payers, prescribers, and patients that the cost and complexity of care associated with specialty medicines is worth the trouble, and now offer patient support programs, free of charge, to patients prescribed their drug. We conducted a secondary, qualitative, interpretive analysis of 24 interviews with leaders of patient groups and members of hospital formulary committees in Australia to describe the work of pharmaceutical company-employed or contracted nurses who provide support to patients prescribed specialty medicines, and to prompt discussion around the policy implications of relying on industry-funded nursing care within publicly funded health systems. Participants affirmed the value of specialist, holistic, person-centered nursing care, but perceived gaps within the public health system related to the availability and provision of nursing care for people living with chronic disease. Consequently, participants described the pharmaceutical industry as addressing health system gaps through sponsorship or direct provision of medication-related nursing care, but recognized that care was contingent on commercial interest. Participants highlighted a number of ethical and policy concerns stemming from industry-funded nursing care of people prescribed specialty medicines related to patient safety, continuity of care, inducement to prescribe, and health equity. This analysis suggests that outsourcing necessary medication-related care to pharmaceutical companies has implications for the health system and equitable, sustainable pharmaceutical policy that extend far beyond the care encounter.

Objective metrics for hand-sewn bowel anastomoses can differentiate novice from expert surgeons.

BACKGROUND: Assessing performance automatically in a virtual reality trainer or from recorded videos is advantageous but needs validated objective metrics. The purpose of this study is to obtain expert consensus and validate task-specific metrics developed for assessing performance in double-layered end-to-end anastomosis. MATERIALS AND METHODS: Subjects were recruited into expert (PGY 4-5, colorectal surgery residents, and attendings) and novice (PGY 1-3) groups. Weighted average scores of experts for each metric item, completion time, and the total scores computed using global and task-specific metrics were computed for assessment. RESULTS: A total of 43 expert surgeons rated our task-specific metric items with weighted averages ranging from 3.33 to 4.5 on a 5-point Likert scale. A total of 20 subjects (10 novices and 10 experts) participated in validation study. The novice group completed the task significantly more slowly than the experienced group (37.67 ± 7.09 vs 25.47 ± 7.82 min, p = 0.001). In addition, both the global rating scale (23.47 ± 4.28 vs 28.3 ± 3.85, p = 0.016) and the task-specific metrics showed a significant difference in performance between the two groups (38.77 ± 2.83 vs 42.58 ± 4.56 p = 0.027) following partial least-squares (PLS) regression. Furthermore, PLS regression showed that only two metric items (Stay suture tension and Tool handling) could reliably differentiate the performance between the groups (20.41 ± 2.42 vs 24.28 ± 4.09 vs, p = 0.037). CONCLUSIONS: Our study shows that our task-specific metrics have significant discriminant validity and can be used to evaluate the technical skills for this procedure.

Bioethics in the Current Climate.

Drawing on insights from feminist epistemology and experience in genomics-related bioethics research, this essay offers three suggestions that may enable bioethics to contribute more persuasively to urgent issues affecting the health and well-being of individuals, communities, and the world they inhabit. First, it suggests that bioethics pay more attention to people's feelings, particularly those that help constitute their self-identities, and to the role of those feelings in their health-relevant behaviors. Further, it proposes conceiving of health-relevant behaviors expansively. Second, it suggests that bioethics advocate for a longer time horizon for the conduct of empirical bioethics research and other types of research addressing complex, systemic factors influencing health. Third, it suggests that bioethics play a larger role in illuminating and applauding the evolving nature of scientific knowledge.

Development and Validation of Task-Specific Metrics for the Assessment of Linear Stapler-Based Small Bowel Anastomosis.

INTRODUCTION: Task-specific metrics facilitate the assessment of surgeon performance. This 3-phased study was designed to (1) develop task-specific metrics for stapled small bowel anastomosis, (2) obtain expert consensus on the appropriateness of the developed metrics, and (3) establish its discriminant validity. METHODS: In Phase I, a hierarchical task analysis was used to develop the metrics. In Phase II, a survey of expert colorectal surgeons established the importance of the developed metrics. In Phase III, to establish discriminant validity, surgical trainees and surgeons, divided into novice and experienced groups, constructed a side-to-side anastomosis on porcine small bowel using a linear cutting stapler. The participants' performances were videotaped and rated by 2 independent observers. Partial least squares regression was used to compute the weights for the task-specific metrics to obtain weighted total score. RESULTS: In Phase II, a total of 45 colorectal surgeons were surveyed: 28 with more than 15 years, 13 with 5 to 15 years, and 4 with less than 5 years of experience. The consensus was obtained on all the task-specific metrics in the more experienced groups. In Phase III, 20 subjects participated equally in both groups. The experienced group performed better than the novice group regardless of the rating scale used: global rating scale (p = 0.009) and the task-specific metrics (p = 0.012). After partial least squares regression, the weighted task-specific metric score continued to show that the experienced group performed better (p < 0.001). CONCLUSION: Task-specific metric items were developed based on expert consensus and showed good discriminant validity compared with a global rating scale between experienced and novice operators. These items can be used for evaluating technical skills in a stapled small bowel anastomosis model.

Experts identified warning signs of fraudulent research: a qualitative study to inform a screening tool.

OBJECTIVE: Fraudulent research exists but can be difficult to spot. Made-up studies and results can affect systematic reviews and clinical guidelines, causing harm through incorrect treatments and practices. Our aim was to explore indicators of research fraud that could be included in a screening tool to identify potentially problematic studies warranting a closer scrutiny. STUDY DESIGN AND SETTING: We conducted a qualitative international interview study, purposively recruiting participants with experience and/or expertise in research integrity, systematic reviews, biomedical publishing, or whistle-blowing research fraud. We used a thematic analysis to identify major concepts and ideas. RESULTS: We contacted 49 potential participants and interviewed 30 from 12 countries. Participants described research fraud as a growing concern, with a lack of widely accessible resources or education to assist in flagging problematic studies. They discussed early warning signs that could be contained in a screening tool for use either prepublication or postpublication. We did not speak to participants from indexing services, information software/analytics companies, or the public. Our suggested screening tools are empirically derived but are preliminary and not validated. CONCLUSION: A practical tool of early warning signs for research fraud would be useful for peer reviewers, editors, publishers, and systematic reviewers.

Disclosure, transparency, and accountability: a qualitative survey of public sector pharmaceutical committee conflict of interest policies in the World Health Organization South-East Asia Region.

BACKGROUND: Weak governance over public sector pharmaceutical policy and practice limits access to essential medicines, inflates pharmaceutical prices, and wastes scarce health system resources. Pharmaceutical systems are technically complex and involve extensive interactions between the private and public sectors. For members of public sector pharmaceutical committees, relationships with the private sector can result in conflicts of interest, which may introduce commercial biases into decision-making, potentially compromising public health objectives and health system sustainability. We conducted a descriptive, qualitative study of conflict of interest policies and practices in the public pharmaceutical sector in ten countries in the World Health Organization (WHO) South-East Asia Region (SEAR) (Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste) between September 2020 and March 2021. RESULTS: We identified 45 policy and regulatory documents and triangulated documentary data with 21 expert interviews. Key informants articulated very different governance priorities and conflict of interest concerns depending on the features of their country's pharmaceutical industry, market size, and national economic objectives related to the domestic pharmaceutical industry. Public sector pharmaceutical policies and regulations consistently contained provisions for pharmaceutical committee members to disclose relevant interests, but contained little detail about what should be declared, when, and how often, nor whether disclosures are evaluated and by whom. Processes for preventing or managing conflicts of interest were less well developed than those for disclosure except for a few key procurement processes. Where processes for managing conflicts of interest were specified, the dominant strategy was to recuse committee members with a conflict of interest from relevant work. Policies rarely specified that committee members should divest or otherwise be free from conflicts of interest. CONCLUSIONS: Robust processes for conflict of interest prevention and management could ensure the integrity of decision-making and build public trust in pharmaceutical processes to achieve public health objectives. Upstream approaches including supportive legislative frameworks, the creation of oversight bodies, and strengthening regulatory institutions can also contribute to building cultures of transparency, accountability, and trust.

Microsampling to support pharmacokinetic clinical studies in pediatrics.

BACKGROUND: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden. METHODS: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions. RESULTS: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain. CONCLUSIONS: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies. IMPACT: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients.