Publications
18 results found
Hohenschurz-Schmidt D, Phalip J, Chan J, et al., 2024, Placebo analgesia in physical and psychological interventions: systematic review and meta-analysis of three-armed trials, European Journal of Pain, Vol: 28, Pages: 513-531, ISSN: 1090-3801
BACKGROUND: The magnitude of placebo effects from physical and psychological 'sham' is unknown but could impact efficacy trials and treatment understanding. To quantify placebo effects, this systematic review of three-armed randomised controlled trials (RCTs) of physical and psychological interventions for pain compared outcomes in 'sham' control intervention and non-exposure arms. METHODS: RCTs with treatment, 'sham' control intervention, and non-exposure groups were included, enrolling adults with any pain. A protocol was pre-registered (PROSPERO: CRD42023413324), and twelve databases searched from 2008 to July 2023. Trial methods and blinding were analysed descriptively and risk of bias assessed. Meta-analysis of pain measures at short-, medium- and long-term was performed with random-effects models of standardised mean differences (SMD).Studies were sub-grouped according to control intervention type. RESULTS: Seventeen RCTs were included. The average short-term placebo effect was small (0.21 SMD, 0.1-0.33 95% CI, p = 0.0002, 1440 participants). It showed no heterogeneity (Tau2 = 0.1, I2 = 11%, p = 0.3), preventing meta-regression analyses of effect modifiers. However, sub-group analyses revealed larger placebo effects in manual control interventions compared to disabled devices and miscellaneous control interventions. Overall, placebo analgesia accounted for 39% of treatments' short-term effectiveness. No placebo effects were found at medium-term (7 RCTs, 381 participants) or long-term follow-up (3 RCTs, 173 participants). CONCLUSIONS: The observed placebo analgesia has mechanistic and methodological implications, though its clinical importance may be limited. Control intervention design affects placebo effects, highlighting the importance of considering methodology in RCT interpretation. Review limitations include a small number of long-term studies and sample heterogeneity. SIGNIFICANCE: This systematic
Soliman N, Denk F, 2024, Practical approaches to improving translatability and reproducibility in preclinical pain research., Brain Behav Immun, Vol: 115, Pages: 38-42
Pain research continues to face the challenge of poor translatability of pre-clinical studies. In this short primer, we are summarizing the possible causes, with an emphasis on practical and constructive solutions. In particular, we stress the importance of increased heterogeneity in animal studies; formal or informal pre-registration to combat publication bias; and increased statistical training in order to help pre-clinical scientists appreciate the usefulness of available experimental design and reporting guidelines.
Kemp H, Kumar A, Soliman N, et al., 2023, A systematic review of the prevalence of post amputation and chronic neuropathic pain associated with combat injury in military personnel, Pain, ISSN: 0304-3959
Combat trauma can lead to widespread tissue damage and limb loss. This may result in chronic neuropathic and post amputation pain, including phantom limb pain (PLP) and residual limb pain (RLP). The military population is distinct with respect to demographic, injury, and social characteristics compared with other amputation and trauma cohorts. We undertook a systematic review of studies of military personnel, with a history of combat injury, that reported a prevalence of any type of postamputation pain or chronic neuropathic pain, identified from Embase and MEDLINE databases.Using the inverse variance method with a random-effects model, we undertook a meta-analysis to determine an overall prevalence and performed exploratory analyses to identify the effect of the type of pain, conflict, and time since injury on prevalence. Pain definitions and types of pain measurement tools used in studies were recorded. Thirty-one studies (14,738 participants) were included. The pooled prevalence of PLP, RLP, and chronic neuropathic pain were 57% (95% CI: 46-68), 61% (95% CI: 50-71), and 26% (95% CI: 10-54), respectively. Between-study heterogeneity was high (I2: 94%-98%). Characterisation of duration, frequency, and impact of pain was limited. Factors reported by included studies as being associated with PLP included the presence of RLP and psychological comorbidity. The prevalence of postamputation pain and chronic neuropathic pain after combat trauma is high. We highlight inconsistency of case definitions and terminology for pain and the need for consensus in future research of traumatic injury.
Dixon Smith S, Aldington D, Hay G, et al., 2023, “I did not expect the doctor to treat a ghost”: a systematic review of published reports regarding chronic postamputation pain in British First World War veterans, PAIN Reports, Vol: 8, ISSN: 2471-2531
Limb trauma remains the most prevalent survivable major combat injury. In the First World War, over 700,000 British soldiers received limb wounds and over 41,000 underwent an amputation, creating one of the largest amputee cohorts in history. Postamputation pain affects up to 85% of military amputees, suggesting that up to 33,000 British First World War veterans potentially reported postamputation pain.This qualitative systematic review explores the professional medical conversation around clinical management of chronic postamputation pain in this patient cohort, its development over the 20th century, and how this information was disseminated amongst medical professionals.We searched The Lancet and British Medical Journal archives (1914-1985) for reports referring to postamputation pain, its prevalence, mechanisms, descriptors or clinical management. Participants were First World War veterans with a limb amputation, excluding civilians and veterans of all other conflicts. The search identified 9809 potentially relevant texts, of which 101 met the inclusion criteria.Reports emerged as early as 1914 and the discussion continued over the next four decades. Unexpected findings included early advocacy of multidisciplinary pain management, concerns over addiction and the impact of chronic pain on mental health emerging decades earlier than previously thought. Chronic postamputation pain is still a significant issue for military rehabilitation. Similarities between injury patterns in the First World War and recent Iraq and Afghanistan conflicts mean these historical aspects remain relevant to today’s military personnel, clinicians, researchers and policymakers.
Soliman N, Kersebaum D, Lawn T, et al., 2023, Improving neuropathic pain treatment - by rigorous stratification from bench to bedside, JOURNAL OF NEUROCHEMISTRY, ISSN: 0022-3042
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Hohenschurz-Schmidt D, Draper-Rodi DJ, Vase PL, et al., 2023, Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article II): a meta-analysis relating methods to trial results, Pain, Vol: 164, Pages: 509-533, ISSN: 0304-3959
Sham interventions in randomised clinical trials (RCTs) of physical, psychological, and self-management (PPS) therapies for pain are highly variable in design and thought to contribute to poor internal validity. It has, however, not been formally tested whether the extent to which sham controls resemble the treatment under investigation consistently affects trial outcomes, such as effect sizes, differential attrition, participant expectancy, and blinding effectiveness.Placebo or sham-controlled RCTs of PPS interventions of clinical pain populations were searched in twelve databases. The similarity of control interventions to the experimental treatment was rated across 25 features. Meta-regression analyses assessed putative links between employed control interventions, observed effect sizes in pain-related outcomes, attrition, and blinding success.The sample included 198 unique control interventions, dominated by manual therapy and chronic musculoskeletal pain research. Meta-analyses indicated small to moderate benefit of active treatments over control interventions, across subgroups of manual therapies, exercise, and rehabilitation, and psychological intervention trials. Multiple meta-regression modelling demonstrated that similarity between sham control and tested interventions predicted variability in pain-related outcomes, attrition, and blinding effectiveness. Influential were differences relating to the extent of intervention exposure, participant experience, and treatment environments.The results support the supposed link between blinding methods and effect sizes, based on a large and systematically sourced overview of methods. Challenges to effective blinding are, however, complex, and often difficult to discern from trial reports. Nonetheless, these insights have the potential to change trial design, conduct, and reporting and will inform guideline development.
Zhang XY, Diaz-delCastillo M, Kong L, et al., 2023, A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain., PLoS One, Vol: 18
Thigmotaxis is an innate predator avoidance behaviour of rodents. To gain insight into how injury and disease models, and analgesic drug treatments affect thigmotaxis, we performed a systematic review and meta-analysis of studies that assessed thigmotaxis in the open field test. Systematic searches were conducted of 3 databases in October 2020, March and August 2022. Study design characteristics and experimental data were extracted and analysed using a random-effects meta-analysis. We also assessed the correlation between thigmotaxis and stimulus-evoked limb withdrawal. This review included the meta-analysis of 165 studies We report thigmotaxis was increased in injury and disease models associated with persistent pain and this increase was attenuated by analgesic drug treatments in both rat and mouse experiments. Its usefulness, however, may be limited in certain injury and disease models because our analysis suggested that thigmotaxis may be associated with the locomotor function. We also conducted subgroup analyses and meta-regression, but our findings on sources of heterogeneity are inconclusive because analyses were limited by insufficient available data. It was difficult to assess internal validity because reporting of methodological quality measures was poor, therefore, the studies have an unclear risk of bias. The correlation between time in the centre (type of a thigmotactic metric) and types of stimulus-evoked limb withdrawal was inconsistent. Therefore, stimulus-evoked and ethologically relevant behavioural paradigms should be viewed as two separate entities as they are conceptually and methodologically different from each other.
Zhang XY, Barakat A, Diaz-delCastillo M, et al., 2022, A systematic review and meta-analysis of studies in which burrowing behaviour was assessed in rodent models of disease associated persistent pain, Pain, Vol: 163, Pages: 2076-2102, ISSN: 0304-3959
Burrowing behaviour is employed to assess pain-associated behaviour in laboratory rodents. To gain insight in how models of disease associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (NSAID and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation (R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin and naproxen showed reduced burrowing behaviour at high doses, while ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease associated pain.
Hohenschurz-Schmidt D, Draper-Rodi DJ, Vase PL, et al., 2022, Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (Article I): a systematic review and description of methods, Pain, Vol: Publish Ahead of Print, ISSN: 0304-3959
Blinding is challenging in randomised controlled trials (RCTs) of physical, psychological, and self-management therapies (PPS) for pain, mainly due to their complex and participatory nature. To develop standards for the design, implementation, and reporting of control interventions in efficacy and mechanistic trials, a systematic overview of currently employed sham interventions and other blinding methods was required.Twelve databases were searched for placebo or sham controlled RCTs of PPS treatments in a clinical pain population. Screening and data extraction were performed in duplicate, and trial features, description of control methods and their similarity to the active intervention under investigation were extracted (protocol registration ID: CRD42020206590).The review included 198 unique control interventions, published between 2008 and December 2021. Most trials studied people with chronic pain, and more than half were manual therapy trials. The described control interventions ranged from clearly modelled based on the active treatment, to largely dissimilar control interventions. Similarity between control and active interventions was more frequent for certain aspects (e.g., duration and frequency of treatments) than others (e.g., physical treatment procedures and patient sensory experiences). We also provide an overview of additional, potentially useful methods to enhance blinding, as well as the reporting of processes involved in developing control interventions.A comprehensive picture of prevalent blinding methods is provided, including a detailed assessment of the resemblance between active and control interventions. These findings can inform future developments of control interventions in efficacy and mechanistic trials and best-practice recommendations.
Haroutounian S, Arendt-Nielsen L, Belton J, et al., 2021, International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management, Pain, Vol: 162, Pages: S117-S124, ISSN: 0304-3959
The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.
Finn DP, Haroutounian S, Hohmann AG, et al., 2021, Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies, Pain, Vol: 162, Pages: S5-S25, ISSN: 0304-3959
This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
Soliman N, Haroutounian S, Hohmann AG, et al., 2021, A systematic review and meta-analysis of cannabis-based medicines, cannabinoids and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain., Pain, Vol: 162, Pages: S26-S44, ISSN: 0304-3959
ABSTRACT: We report a systematic review and meta-analysis of studies which assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference (SMD) effect size for each comparison and performed a random effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86 %). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective CB1, CB2, non-selective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol; THC), and PPAR-alpha agonists (predominantly palmitoylethanolamide; PEA) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MGL) inhibitors and cannabidiol (CBD) significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low, therefore the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.
Bahor Z, Liao J, Currie G, et al., 2021, Development and uptake of an online systematic review platform: the early years of the CAMARADES Systematic Review Facility (SyRF), BMJ Open Science, Vol: 5, ISSN: 2398-8703
Preclinical research is a vital step in the drug discovery pipeline and more generally in helping to better understand human disease aetiology and its management. Systematic reviews (SRs) can be powerful in summarising and appraising this evidence concerning a specific research question, to highlight areas of improvements, areas for further research and areas where evidence may be sufficient to take forward to other research domains, for instance clinical trial. Guidance and tools for preclinical research synthesis remain limited despite their clear utility. We aimed to create an online end-to-end platform primarily for conducting SRs of preclinical studies, that was flexible enough to support a wide variety of experimental designs, was adaptable to different research questions, would allow users to adopt emerging automated tools and support them during their review process using best practice. In this article, we introduce the Systematic Review Facility (https://syrf.org.uk), which was launched in 2016 and designed to support primarily preclinical SRs from small independent projects to large, crowdsourced projects. We discuss the architecture of the app and its features, including the opportunity to collaborate easily, to efficiently manage projects, to screen and annotate studies for important features (metadata), to extract outcome data into a secure database, and tailor these steps to each project. We introduce how we are working to leverage the use of automation tools and allow the integration of these services to accelerate and automate steps in the systematic review workflow.
Zhang XY, Vollert J, Sena ES, et al., 2021, A protocol for the systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain, BMJ Open Science, Vol: 5, ISSN: 2398-8703
<jats:sec><jats:title>Objective</jats:title><jats:p>Thigmotaxis is an innate predator avoidance behaviour of rodents and is enhanced when animals are under stress. It is characterised by the preference of a rodent to seek shelter, rather than expose itself to the aversive open area. The behaviour has been proposed to be a measurable construct that can address the impact of pain on rodent behaviour. This systematic review will assess whether thigmotaxis can be influenced by experimental persistent pain and attenuated by pharmacological interventions in rodents.</jats:p></jats:sec><jats:sec><jats:title>Search strategy</jats:title><jats:p>We will conduct search on three electronic databases to identify studies in which thigmotaxis was used as an outcome measure contextualised to a rodent model associated with persistent pain. All studies published until the date of the search will be considered.</jats:p></jats:sec><jats:sec><jats:title>Screening and annotation</jats:title><jats:p>Two independent reviewers will screen studies based on the order of (1) titles and abstracts, and (2) full texts.</jats:p></jats:sec><jats:sec><jats:title>Data management and reporting</jats:title><jats:p>For meta-analysis, we will extract thigmotactic behavioural data and calculate effect sizes. Effect sizes will be combined using a random-effects model. We will assess heterogeneity and identify sources of heterogeneity. A risk-of-bias assessment will be conducted to evaluate study quality. Publication bias will be assessed using funnel plots, Egger’s regression and trim-and-fill analysis. We will also extract stimulus-evoked limb withdrawal data to assess its correlation with thigmotaxis in the same animals. The evidence obtained will provide a comprehensive understanding of the strengths and limitations of using thigmotactic outcome measure in animal pain
Bannach-Brown A, Hair K, Bahor Z, et al., 2021, Technological advances in preclinical meta-research., BMJ Open Science, Vol: 5, Pages: 1-10, ISSN: 2398-8703
Soliman N, Rice A, Vollert J, 2020, A practical Guide to preclinical systematic review and meta-analysis, Pain, Vol: 161, Pages: 1949-1954, ISSN: 0304-3959
Preclinical systematic reviews (SRs) and meta-analyses (MAs) are important research activities to address the translational challenges of pain research. SRs provide empirical evidence to gain knowledge, inform future research agendas and grant applications concurrent to developing researchers’ professional skills. SRs are an effective approach to consolidating high volume, rapidly accruing and often conflicting research on a specific topic. Designed to address a specific research question, SRs use predefined methods to identify, select and critically appraise all available and relevant literature to answer that question in an unbiased manner [18]. This structured approach distinguishes SRs from narrative reviews. Where appropriate a MA can follow, whereby quantitative data are extracted and statistical techniques are used to summarise the outputs. Together, a SR and MA can be conducted to assess the quality of experimental design, conduct, analysis and reporting and the reliability of all available and relevant data [45]. Through decades of innovation by the Cochrane Collaboration and others, SRs and MAs now lie at the centre of clinical evidence. The information provided has fundamentally revolutionised clinical medicine at all levels from informing policy and funding decisions to determining optimal treatments for individual patients. Before a clinical research project or funding application, it is best practise to conduct a SR to ascertain what is already known and to identify knowledge gaps. In the preclinical setting SRs are relatively novel, partially because of inherent complexities and resource requirements for processing the large number and diverse preclinical publications; paradoxically a strong justification for SRs because they provide the means to synthesise evidence from heterogeneous studies. In some fields they are gaining popularity (e.g. stroke [37]) and feasibility is improving with technical advances e.g. online review software, ma
Soliman N, Okuse K, Rice A, 2019, VGF, a biomarker and potential target for the treatment of neuropathic pain?, PAIN Reports, Vol: 4, Pages: 1-14, ISSN: 2471-2531
Neuropathic pain remains an area of considerable unmet medical need. A persistentchallenge in the management of neuropathic pain is to target the specific mechanismsleading to a change from normal to abnormal sensory perception while ensuring thatthe defensive pain perception remains intact. Targeting VGF-derived neuropeptidesmay offer this opportunity. VGF was first identified in 1985 and is highly expressedfollowing nerve injury and inflammation in neurons of both the peripheral and centralnervous system. Subsequent studies implicate the vgf gene and its products in painpathways. This narrative review was supported by a systematic search to identify,select and critically appraise all relevant research investigating the role of VGF-derivedneuropeptides in pain pathways. It predominantly focuses on in vivo investigations ofthe role of VGF in the initiation and maintenance of neuropathic pain. VGF expressionlevels are very low under normal physiological conditions and nerve injury results inrapid and robust upregulation, increasing mechanical and thermal hypersensitivity.The identification of the two complement receptors with which VGF-neuropeptidesinteract suggests a novel interplay of neuronal and immune signalling mediators. Theunderstanding of the molecular mechanisms and signalling events by which VGFderivedactive neuropeptides exert their physiological actions is in its infancy. Futurework should aim to improve understanding of the downstream consequences of VGFneuropeptidesthereby providing novel insights into pain mechanisms potentiallyleading to the identification of novel therapeutic targets.
Soliman N, Hohmann AG, Haroutounian S, et al., 2019, A protocol for the systematic review and meta-analysis of studies in which cannabinoids were tested for antinociceptive effects in animal models of pathological or injury-related persistent pain., PAIN Reports, Vol: 4, Pages: 1-6, ISSN: 2471-2531
Introduction: The International Association for the Study of Pain has established a global task force to comprehensively investigate the use of cannabinoids and cannabis-based medicines for pain management. This systematic review, the first in this field, will assess the preclinical literature that investigates the antinociceptive effects of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators in animal models of tissue damage, inflammation, or neuropathy. Methods: A systematic electronic search of 3 online databases will identify relevant studies in which cannabinoids, cannabis-based medicines, and endocannabinoid system modulators have been tested in animal models of injury-related or pathological persistent pain. Data will be extracted for pain-associated behavioural outcomes, study design, and the reporting of measures to avoid bias. Standardised mean difference meta-analysis will be used to provide summary estimates of efficacy, with the effects of study quality and study design explored using stratified meta-analysis. Perspective: The evaluation of the preclinical evidence will quantify the antinociceptive effects of cannabinoids on pain behaviour in animal models of pathological pain in an effort to quantify the presence and prevalence of analgesic efficacy. It will also provide an understanding of the strengths and weaknesses of the preclinical field and inform an agenda for future research.
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