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BackgroundMonoclonal antibodies against tumour necrosis factor (TNF) markedly reduce inflammation and disease activity in rheumatoid arthritis; however, the mechanisms through which they affect pain are not fully understood.AimsThe aim of this study was to investigate how monoclonal antibodies against TNF alter pain processing and to determine whether neuroimaging can be used as a marker of treatment efficacy and a predictor of treatment response.MethodsFunctional magnetic resonance imaging was used to study the neural correlates of clinically-relevant pain evoked by pressing the most painful joint of the right hand and experimental pain evoked by a thermal stimulus applied to the right forearm. A flashing checkerboard was used as a control stimulus. Patients with severe rheumatoid arthritis, qualifying for the anti-TNF treatment, were scanned before the beginning of the therapy and then approximately one and six months after the first injection.ResultsTNF inhibition was associated with a marked reduction in pain ratings, inflammation, disease activity as well as depression and catastrophising scores. Effective treatment was linked with less pressure-evoked brain activation in the regions involved in the processing of the sensory aspect of pain and in the limbic structures. Baseline pressure-evoked activation in the thalamus predicted future response to treatment. There was no reduction in heat-evoked brain activation; on the contrary, there was an increase in the activation in the precuneus, which is involved in interoception. There were no differences in response to the visual stimulus.ConclusionsTNF inhibition strongly reduces brain activation in response to clinically relevant pressure pain but not experimental heat pain and these changes reflect the decrease of nociceptive input from the periphery due to the reduction of inflammation as well as central changes in pain modulation. Neuroimaging methods have the potential to explain and predict treatment effects in inflammatory pain conditions.

Refereed/Peer-reviewed Control interventions (often called “sham,” “placebo,” or “attention controls”) are essential for studying the efficacy or mechanism of physical, psychological, and self-management interventions in clinical trials. This article presents core recommendations for designing, conducting, and reporting control interventions to establish a quality standard in non-pharmacological intervention research. A framework of additional considerations supports researchers’ decision making in this context. We also provide a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour.

Randomised placebo-controlled trials (RPCTs) are the gold standard for evaluating novel treatments. However, this design is rarely used in the context of orthopaedic interventions where participants are assigned to a real or placebo surgery. The present study examines attitudes towards RPCTs for orthopaedic surgery among 687 orthopaedic surgeons across the USA. When presented with a vignette describing an RPCT for orthopaedic surgery, 52.3% of participants viewed it as ‘completely’ or ‘mostly’ unethical. Participants were also asked to rank-order the value of five different types of evidence supporting the efficacy of a surgery, ranging from RPCT to an anecdotal report. Responses regarding RPCTs were polarised with 26.4% viewing it as the least valuable (even less valuable than an anecdote) and 35.7 .% viewing it as the most valuable. Where equipoise exists, if we want to subject orthopaedic surgeries to the highest standard of evidence (RPCTs) before they are implemented in clinical practice, it will be necessary to educate physicians on the value and ethics of placebo surgery control conditions. Otherwise, invasive procedures may be performed without any benefits beyond possible placebo effects.

In recent years, patient-reported outcome measures (PROMs) have become increasingly popular in clinical practice and clinical trials. In this paper, we highlight the need for introducing measures to control for the bias associated with these inherently subjective measures and combining PROMs with objective outcomes, which do not depend on judgement, experience or performance. PROMs measure the subjective elements of patients’ conditions, including health-related quality of life, pain intensity, activity limitations, participation restrictions, satisfaction or adherence to treatment and help to evaluate the burden of disease and treatment from patients’ perspectives.1 Originally, PROMs were used in pharmacological research to assess treatment effects in conditions such as cancer, in cases where the cure was not possible, and quality of life became the primary concern.2 In the last 20 years, the use of PROMs has increased considerably,1 3 and, currently, those outcomes are used to assess the effects of treatment and quality of care2 and to evaluate policies3 and to inform health economics.4 One of the factors that contributed to the popularity of PROMs was their recognition by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a measure of treatment efficacy.1 5 6 The FDA and the EMA define PROMs as any outcomes related to the patient’s health or treatment that is evaluated directly by the patient, without any interpretation by a doctor or anyone else.1 6 According to this definition, and in contrast to common perception, these outcomes do not necessarily measure what is the most important to patients or health itself.7 8 ### The role of PROMs The main role of PROMs …

Background: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. Methods: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. Results: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P P P =0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P P P =0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP ( P Conclusions: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Small vessel disease is associated with age, mean blood pressure (MAP) and blood pressure pulsatility (PP). We used data from the UK Biobank cohort study to determine the relative importance of MAP versus PP driving white matter injury within individual white matter tracts, particularly in the anterior and posterior vascular territory. The associations between blood pressure and diffusion indices in 27 major tracts were analysed using unadjusted and fully-adjusted general linear models and mixed-effect linear models. Blood pressure and neuroimaging data were available for 37,041 participants (mean age 64+/−7.5 years, 53% female). In unadjusted analyses, MAP and PP were similarly associated with diffusion indices in the anterior circulation. In the posterior circulation, the associations were weaker, particularly for MAP. In fully-adjusted analyses, MAP remained associated with all diffusion indices in the anterior circulation, independently of age. In the posterior circulation, the effect of MAP became protective. PP remained associated with greater mean diffusivity and extracellular free water diffusion in the anterior circulation and all diffusion indices in the posterior circulation. There was a significant interaction between PP and age. This implies discordant mechanisms for chronic white matter injury in different brain regions and potentially in the associated stroke risks.

This commentary refers to doi:10.1093/eurheartj/ehaa756; ‘On cerebrotoxicity of antihypertensive therapy and risk factor cosmetics’, by F.H. Messerli et al., doi:10.1093/eurheartj/ehaa971; ‘Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study’, by K.A. Wartolowska and A.J.S. Webb, doi:10.1093/eurheartj/ehaa756 and the discussion piece ‘Cerebrotoxicity of antihypertensive therapy in the UK Biobank Cohort Study’, by F.H. Messerli et al., doi:10.1093/eurheartj/ehab567.

Background Cerebral small vessel disease (SVD) is associated with increased cerebrovascular pulsatility, endothelial dysfunction, and impaired vascular reactivity. Vasodilating phosphodiesterase inhibitors may improve cardiovascular pulsatility and reactivity, and potentially reduce progression of SVD. Hypothesis: Sildenafil, a PDE5 inhibitor, will reduce cerebrovascular pulsatility and increase cerebrovascular reactivity compared to placebo, and is non-inferior to cilostazol, a PDE3 inhibitor. Methods OxHARP is a randomised, double-blind, crossover trial of sildenafil 50 mg thrice daily, cilostazol 100 mg twice daily and placebo in 75 patients with mild to moderate small vessel disease and a previous lacunar or cryptogenic stroke or TIA. Participants undergo a physiological assessment at baseline and on each treatment, including transcranial Doppler ultrasound (TCD, DWL DopplerBox) to assess cerebrovascular pulsatility and reactivity to 4–6% carbon dioxide. In up to 60 patients, cerebrovascular pulsatility, perfusion and reactivity will also be assessed by MRI. Outcome measures The primary outcome is difference in middle cerebral artery pulsatility (Gosling’s Pulsatility Index, PI) after 3 weeks of sildenafil versus placebo. Secondary outcomes including non-inferiority of sildenafil vs cilostazol in effects on PI, percentage increase in MCA blood flow velocity and BOLD-fMRI response during inhalation of 4–6% carbon dioxide. Discussion Reduction in cerebral pulsatility and increased cerebrovascular reactivity during treatment with sildenafil would indicate potential benefit to prevent progression of SVD, suggesting a need for trials with clinical outcomes. Trial Registration OxHARP is registered with ClinicalTrials.org, NCT03855332

Purpose To evaluate the diagnostic accuracy of Gallium-68 prostate-specific membrane antigen positron emission tomography-computed tomography (68Ga-PSMA PET/CT) compared with multiparametric magnetic resonance imaging (mpMRI) for detection of metastatic lymph nodes in intermediate to high-risk prostate cancer (PCa). Methods PRISMA-compliant systematic review updated to September 2020 was performed to identify studies that evaluated the diagnostic performance of 68Ga-PSMA PET/CT and mpMRI for detection of metastatic lymph nodes in the same cohort of PCa patients using histopathologic examination as a reference standard. The quality of each study was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) instrument. STATA version 16.0 was used to obtain the pooled estimates of diagnostic accuracy for per-patient and per-lesion analyses. Heterogeneity in the accuracy estimates was explored by reviewing the generated forest plots, summary receiver operator characteristic (SROC) curves, hierarchical SROC plots, chi-squared test, heterogeneity index, and Spearman’s correlation coefficients. Results Six studies, which included 476 patients, met the eligibility criteria for per-patient analysis and four of these studies, reporting data from 4859 dissected lymph nodes, were included in the per-lesion analysis. In the per-patient analysis (N = 6), the pooled sensitivity and specificity for 68Ga-PSMA PET/CT were 0.69 and 0.93, and for mpMRI the pooled sensitivity and specificity were 0.37 and 0.95. In the per-lesion analysis (N = 4), the pooled sensitivity and specificity for 68Ga-PSMA PET/CT were 0.58 and 0.99, and for mpMRI the pooled sensitivity and specificity were 0.44 and 0.99. There was high heterogeneity and a threshold effect in outcomes. A sensitivity analysis demonstrated that the pooled estimates were stable when excluding studies with patient selection concerns, whereas the variances of the pooled estimates became significant, and the characteristics of heterogeneity changed when excluding studies with concerns about index imaging tests. Conclusion Both imaging techniques have high specificity for the detection of nodal metastases of PCa. 68Ga-PSMA PET/CT has the advantage of being more sensitive and making it possible to detect distant metastases during the same examination. These modalities may play a complementary role in the diagnosis of PCa. Given the paucity of data and methodological limitations of the included studies, large scale trials are necessary to confirm their clinical values.

Supplemental Digital Content is available in the text., Small vessel disease and related stroke and dementia risks are linked to aging and hypertension, but it is unclear whether the pulsatile or steady blood pressure (BP) component is more important for the development of macrostructural hyperintensities and microstructural white matter damage. This was a cross-sectional analysis of the UK Biobank cohort study of community-based adults from 22 UK centers. Linear associations were determined between neuroimaging markers (white matter hyperintensity [WMH] volume and diffusion imaging indices) and mean arterial pressure and pulse pressure (PP), both unadjusted and adjusted for age, sex, cardiovascular risk factors, antihypertensive medication, BP source, and assessment center. In 37 041 participants aged 45 to 82 years (53% female), univariable analyses demonstrated that increases in both BP components were associated with greater WMH volume and white matter injury on diffusion indices, with a larger effect for PP (standardized effect size for WMH: mean arterial BP: 0.182 [95% CIs, 0.170–0.193]; PP: 0.285 [95% CIs, 0.274–0.296]). In multivariable analyses, associations with mean arterial pressure remained similar, but associations with PP diminished, reflecting covariance with age and risk factors (standardized effect size for WMH: mean arterial BP: 0.106 [95% CIs, 0.095–0.117]; PP: 0.011 [95% CIs, −0.001 to 0.023]). The synergistic interaction between PP and age increased the effect of age on WMH and diffusion indices. Both macrostructural and microstructural white matter injury had similar associations with the pulsatile and steady components of hypertension, although PP accentuated the relationship between age and white matter damage.

Supplemental Digital Content is available in the text., Beat-to-beat variability in blood pressure (BP) is associated with recurrent stroke despite good control of hypertension. However, no study has identified rates of progression of beat-to-beat BP variability (BPV), its determinants, or which patient groups are particularly affected, limiting understanding of its potential as a treatment target. In consecutive patients one month after a transient ischaemic attack or nondisabling stroke (Oxford Vascular Study), continuous noninvasive BP was measured beat-to-beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). Repeat assessments were performed at the 5-year follow-up visit and agreement determined by intraclass correlation coefficient. Rates of progression of systolic BPV (SBPV) and diastolic BPV (DBPV) and their determinants were estimated by mixed-effect linear models, adjusted for age, sex, and cardiovascular risk factors. One hundred eighty-eight of 310 surviving, eligible patients had repeat assessments after a median of 5.8 years. Pulse wave velocity was highly reproducible but SBPV and DBPV were not (intraclass correlation coefficient: 0.71, 0.10, and 0.16, respectively), however, all 3 progressed significantly (pulse wave velocity, 2.39%, P

Objective The development of persistent pain following total knee arthroplasty (TKA) is common, but its underlying mechanisms are unknown. The goal of the study was to assess brain grey matter structure and its correlation with function of the nociceptive system in people with good and poor outcomes following TKA. Subjects Thirty-one people with LOW_PAIN ( Methods Grey matter in key brain areas related to nociception was analyzed using voxel-based morphometry (VBM). Nociceptive facilitatory and inhibitory processes were evaluated using quantitative sensory testing (QST). QST scores and grey matter density in prespecified brain regions were compared between the LOW_PAIN and HIGH_PAIN groups. Regression analyses were used to analyze the associations between the grey matter and QST scores. Results There were no between-group differences in QST measures. In the VBM analysis, the HIGH_PAIN group had a higher grey matter density in the right amygdala, right nucleus accumbens, and in the periaqueductal grey (PAG), but lower grey matter density in the dorsal part of the left caudate nucleus. Grey matter density in the right amygdala and PAG correlated positively with temporal summation of pain. Conclusions Persistent pain at six months after TKA is associated with a higher grey matter density in the regions involved in central sensitization and pain-related fear, which may contribute to the development of persistent pain after surgery.

Background\ud \ud Arthroscopic sub-acromial decompression (decompressing the sub-acromial space by removing bone spurs and soft tissue arthroscopically) is a common surgery for subacromial shoulder pain, but its effectiveness is uncertain. We did a study to assess its effectiveness and to investigate the mechanism for surgical decompression.\ud \ud \ud \ud Methods\ud \ud We did a multicentre, randomised, pragmatic, parallel group, placebo-controlled, three-group trial at 32 hospitals in the UK with 51 surgeons. Participants were patients who had subacromial pain for at least 3 months with intact rotator cuff tendons, were eligible for arthroscopic surgery, and had previously completed a non-operative management programme that included exercise therapy and at least one steroid injection. Exclusion criteria included a full-thickness torn rotator cuff. We randomly assigned participants (1:1:1) to arthroscopic subacromial decompression, investigational arthroscopy only, or no treatment (attendance of one reassessment appointment with a specialist shoulder clinician 3 months after study entry, but no intervention). Arthroscopy only was a placebo as the essential surgical element (bone and soft tissue removal) was omitted. We did the randomisation with a computer-generated minimisation system. In the surgical intervention groups, patients were not told which type of surgery they were receiving (to ensure masking). Patients were followed up at 6 months and 1 year after randomisation; surgeons coordinated their waiting lists to schedule surgeries as close as possible to randomisation. The primary outcome was the Oxford Shoulder Score (0 [worst] to 48 [best]) at 6 months, analysed by intention to treat. The sample size calculation was based upon a target difference of 4·5 points (SD 9·0). This trial has been registered at ClinicalTrials.gov, number NCT01623011.\ud \ud \ud \ud Findings\ud \ud Between Sept 14, 2012, and June 16, 2015, we randomly assigned 313 patients to treatment groups (106 to decompression surgery, 103 to arthroscopy only, and 104 to no treatment). 24 [23%], 43 [42%], and 12 [12%] of the decompression, arthroscopy only, and no treatment groups, respectively, did not receive their assigned treatment by 6 months. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression mean 32·7 points [SD 11·6] vs arthroscopy mean 34·2 points [9·2]; mean difference −1·3 points (95% CI −3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], mean difference vs decompression 2·8 points [95% CI 0·5–5·2], p=0·0186; mean difference vs arthroscopy 4·2 [1·8–6·6], p=0·0014) but these differences were not clinically important. There were six study-related complications that were all frozen shoulders (in two patients in each group).\ud \ud \ud \ud Interpretation\ud \ud Surgical groups had better outcomes for shoulder pain and function compared with no treatment but this difference was not clinically important. Additionally, surgical decompression appeared to offer no extra benefit over arthroscopy only. The difference between the surgical groups and no treatment might be the result of, for instance, a placebo effect or postoperative physiotherapy. The findings question the value of this operation for these indications, and this should be communicated to patients during the shared treatment decision-making process.\ud \ud \ud \ud Funding\ud \ud Arthritis Research UK, the National Institute for Health Research Biomedical Research Centre, and the Royal College of Surgeons (England).

Objective To examine attitudes of Open Label Placebos (OLP) among a national sample of US orthopedic surgeons. Methods Orthopedic surgeons across the US were invited to participate in a brief online cross-sectional survey; n = 687 participated. The survey included a short vignette of a surgeon using adjunctive OLPs in addition to opioids for postoperative pain management. Participants indicated how ethical and effective they thought OLPs would be in this context, and whether they would personally consider using OLPs. Results Nearly three-quarters (73.9%) of the surgeons considered OLPs ethical. In total, 55.4% and 48.8% of participants said that OLPs would “probably” or “definitely” be effective for Vicodin reduction and pain relief, respectively. However, only 19.2% of participants indicated they were personally willing to consider OLPs, and 59.6% were unwilling to do so. Conclusions Generally, orthopedic surgeons perceive OLPs as both ethical and effective, but would not consider using them in their practice. Further research is needed to identify clinician barriers to OLP use.

The term nocebo effect refers to the harmful outcomes that result from people’s negative beliefs, anticipations, or experiences related to the treatment rather than the pharmacological properties of the treatment. These outcomes may include a worsening of symptoms, a lack of expected improvement, or adverse events, and they may occur after the active treatment and the placebo that is supposed to imitate it. The nocebo effect is always unwanted and may distort estimates of treatment effectiveness and safety; moreover, it may cause discontinuation of therapy or withdrawal from a trial. The nocebo effect may be unintentionally evoked by the explanations given by healthcare professionals during a clinical consultation or consent procedures, or by information from other patients, the media, or the Internet. Moreover, it may be a consequence of previous bad experiences with the treatment, through learning and conditioning, and the conditioning may happen without patients’ conscious awareness. In trial settings, a study design, for example lack of blinding, may introduce bias from the nocebo effect. Unlike the placebo effect, which is usually taken into consideration while interpreting treatment outcomes and controlled for in clinical trials, the nocebo effect is under-recognised by clinical researchers and clinicians. This is worrying, because the nocebo phenomenon is common and may have potentially negative consequences for the results of clinical treatment and trials. It is therefore important that doctors and medical researchers consider any potential nocebo effect while assessing the treatment effect and try to minimise it through careful choice and phrasing of treatment-related information given to patients.

Objective: To investigate whether structural changes are present in the cortical and subcortical gray matter of the brains of patients with rheumatoid arthritis (RA). Methods: We used two surface‐based style morphometry analysis programs and a voxel‐based style analysis program to compare high‐resolution structural magnetic resonance imaging data obtained for 31 RA patients and 25 age‐ and sex‐matched healthy control subjects. Results We observed an increase in gray matter content in the basal ganglia of RA patients, mainly in the nucleus accumbens and caudate nucleus. There were no differences in the cortical gray matter. Moreover, patients had a smaller intracranial volume. Conclusion: Our results suggest that RA is associated with changes in the subcortical gray matter rather than with cortical gray matter atrophy. Since the basal ganglia play an important role in motor control as well as in pain processing and in modulating behavior in response to aversive stimuli, we suggest that these changes may result from altered motor control or prolonged pain processing. The differences in brain volume may reflect either generalized atrophy or differences in brain development.

Summary Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to ‘personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.

Objective To evaluate the impact of the QuinteT Recruitment Intervention (QRI) on recruitment in challenging randomized controlled trials (RCTs) that have applied the intervention. The QRI aims to understand recruitment difficulties and then implements “QRI actions” to address these as recruitment proceeds. Study Design and Setting A mixed-methods study, comprising (1) before-and-after comparisons of recruitment rates and the numbers of patients approached and (2) qualitative case studies, including documentary analysis and interviews with RCT investigators. Results Five UK-based publicly funded RCTs were included in the evaluation. All recruited to target. Randomized controlled trial 2 and RCT 5 both received up-front prerecruitment training before the intervention was applied. Randomized controlled trial 2 did not encounter recruitment issues and recruited above target from its outset. Recruitment difficulties, particularly communication issues, were identified and addressed through QRI actions in RCTs 1, 3, 4, and 5. Randomization rates significantly improved after QRI action in RCTs 1, 3, and 4. Quintet Recruitment Intervention actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in the number of patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of and reportedly changed their practices after QRI action. Conclusion There is promising evidence to suggest that the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations.

Clinical pain is difficult to study using standard Blood Oxygenation Level Dependent (BOLD) magnetic resonance imaging because it is often ongoing and, if evoked, it is associated with stimulus-correlated motion. Arterial spin labelling (ASL) offers an attractive alternative. This study used arm repositioning to evoke clinically-relevant musculoskeletal pain in patients with shoulder impingement syndrome. Fifty-five patients were scanned using a multi post-labelling delay pseudo-continuous ASL (pCASL) sequence, first with both arms along the body and then with the affected arm raised into a painful position. Twenty healthy volunteers were scanned as a control group. Arm repositioning resulted in increased perfusion in brain regions involved in sensory processing and movement integration, such as the contralateral primary motor and primary somatosensory cortex, mid- and posterior cingulate cortex, and, bilaterally, in the insular cortex/operculum, putamen, thalamus, midbrain and cerebellum. Perfusion in the thalamus, midbrain and cerebellum was larger in the patient group. Results of a post hoc analysis suggested that the observed perfusion changes were related to pain rather than arm repositioning. This study showed that ASL can be useful in research on clinical ongoing musculoskeletal pain but the technique is not sensitive enough to detect small differences in perfusion.

Objectives EBM DataLab is a team that aims to produce tools from data, rather than just academic publications. We have a multidisciplinary approach that combines the skills of software engineers, clinicians and academics. In this workshop we will give an overview covering how to make effective interactive services driven by data, through: Providing an overview of the software and services which can be used to create your own data–driven tools. Demonstrating examples from the work of the EBM DataLab. Providing an opportunity for attendees to discuss their own ideas or experiences related to data–driven tools. Method In this session you will learn the very basics about a range of useful software and services including Python, pandas and iPython notebooks, GitHub, Google Analytics, Google Sheets, Google Forms, API’s (for Scopus, PubMed, and Web of Science), SQL databases such as BigQuery and Postgres, and graphical tools such as Tableau and d3. We will demonstrate the creative use of these tools with worked examples from our recent output including the Retractobot, various trials trackers, OpenPrescribing long term trends, the Drug Tariff explorer, and more. Results Attendees should leave this workshop with a better grasp of how to identify user needs, select the appropriate software or services for the job, design tools to be deliverable and impactful, manage the development cycle from prototyping to launch, and carry out the basic process of user testing. Conclusions Simple yet engaging presentation of data that allows people to act on it can be a critical step in disseminating evidence and improving quality of care. Live updating dynamic tools can keep information at the cutting-edge and provide a platform that provides real and enduring value to users. There are great resources available that can allow researchers to quickly and efficiently turn their findings into public-facing tools. We hope this workshop will empower attendees to begin presenting and sharing their data in new and effective ways in order to promote positive change in their respective fields.

Inferences about the effects of treatments, including surgical treatments, rely on making comparisons. These comparisons may be with patient’s symptoms before a treatment has been applied. For example, the return of hearing after puncturing the ear drum (tympanotomy) in certain kinds of longstanding deafness can be so dramatic that the change can be confidently ascribed to the treatment.1,2 More usually, treatments have more modest effects, and alternative treatments may differ from each other only slightly, if at all. In these circumstances, disagreements are common about the mechanisms, the magnitude of any effects and the value of a particular treatment. Examples include disputes about different ways of treating wounds,3,4 the timing and methods of limb amputations,5–10 and about lithotripsy as an alternative to lithotomy.11–13

Objectives To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Study Design and Setting Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. Results One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. Conclusions The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., Highlights • Practices commonly used to describe randomisation in RCT recruitment could confuse patients. • Patients found it difficult to comprehend gambling-related metaphors of randomisation. • Computer-agency descriptions led to patients believing they would receive the best treatment.

BackgroundA lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. MethodsWe chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. ResultsWhen compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. ConclusionsFunctional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism.

Pain is a complex and multidimensional experience, which is subjective for an individual and modulated by physiological and psychological factors. Therefore, it is difficult to quantify pain and there are no objective pain measures available at the moment. Neuroimaging provides an objective measure of changes in brain activity related to pain perception. In this review, we demonstrate that pain-related brain activation is complex and can be best studied as a dynamic network of interconnected regions. Finally, we use the placebo and nocebo effects to discuss the factors involved in modulation of pain experience. © 2011 European Federation of International Association for the Study of Pain Chapters.

Background Temporal changes in the placebo arm of randomized controlled trials (RCTs) have not been thoroughly investigated, despite the fact that results of RCTs depend on the comparison between arms. Methods In this update of our earlier systematic review and meta-analysis, we set out to investigate the effect of assessment time and number of visits on the magnitude of change from baseline in the placebo arm of these trials. We used linear mixed-effects models to account for within-trial correlations. Results Across all 47 trials the magnitude of response in the placebo arm did not change with time (β = -0.0070, 95% CI -0.024, 0.010) or visit (β = -0.033, 95% CI -0.082, 0.017) and remained significantly different from baseline for at least 12 months or seven follow-up visits. Change in the placebo arm in trials with subjective outcomes was large (β0 = 0.68, 95% CI 0.53, 0.82) and relatively constant across time (β = -0.0042, 95% CI -0.024, 0.016) and visit (β = -0.029, 95% CI -0.089, 0.031), whereas in trials with objective outcomes the response was smaller (β0 = 0.28, 95% CI 0.11, 0.46) and diminished with time (β = -0.030, 95% CI -0.050, -0.010), but not with visit (β = -0.099, 95% CI -0.30, 0.11). For trials with assessed outcomes, there was no significant effect of time (β = -0.0071, 95% CI -0.026, 0.011) or visit (β = -0.032, 95% CI -0.33, 0.26); however, these results should be interpreted with caution due to the small number of studies, and high clinical heterogeneity between studies. In trials with pain as an outcome, the improvement was significant (β0 = 0.91, 95% CI 0.75, 1.07), but there was no effect of time (β = -0.013, 95% CI -0.06, 0.03) or visit (β = -0.045, 95% CI -0.16, 0.069), and pain ratings remained significantly different from baseline for 12 months or seven visits. Conclusions These results are consistent with our previous findings. In trials with subjective outcomes response in the placebo arm remains large and relatively constant for at least a year, which is interesting considering that this is an effect of a single application of an invasive procedure. The lack of effect of time and visit number on subjective outcomes raises further questions regarding whether the observed response is the result of placebo effect or the result of bias. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2070-9) contains supplementary material, which is available to authorized users.

Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing-of expertise and/or funding-has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies. In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners. Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: (1) the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (2) clinically important research question; (3) the risk to patients is minimised and reasonable; (4) there is uncertainty about treatment allocation rather than deception; (5) there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and (6) ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial (1) should be sufficiently powered and (2) standardised so that its results are valid, (3) consent should be valid, (4) the standard treatment or rescue medication should be provided if possible, and (5) after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association.

Neuroimaging makes it possible to study pain processing beyond the peripheral nervous system, at the supraspinal level, in a safe, noninvasive way, without interfering with neurophysiological processes. In recent years, studies using brain imaging methods have contributed to our understanding of the mechanisms responsible for the development and maintenance of chronic pain. Moreover, neuroimaging shows promising results for analgesic drug development and in characterizing different types of pain, bringing us closer to development of mechanism-based diagnoses and treatments for the chronic pain patient.

Although depressive mood is an important psychological determinate of chronic pain, the neural circuitry that mediates its influence on the pain experience is largely unknown. We used functional magnetic resonance imaging (FMRI) to investigate the neurophysiological interactions between depressive symptoms and disease-relevant pain in rheumatoid arthritis (RA) patients. RA is associated with chronic joint pain and swelling, but peripheral joint pathology often does not fully explain the amount of pain a patient experiences. We investigated the neural circuitry that relates to joint pain and depressive symptoms and contrasted this with experimental heat pain. We hypothesized that (1) depressive symptoms influence the cerebral processing of provoked joint pain in RA, and (2) the interaction of depressive symptoms with pain processing contributes to the pain RA patients experience on a daily basis. Twenty patients underwent whole brain FMRI during which disease-relevant joint pain was provoked. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The tender-to-swollen joint ratio (T/S) was assessed as one component of the patients' clinical pain. BDI scores correlated significantly with T/S and medial prefrontal cortex (MPFC) activation during provoked joint pain. The association between BDI scores and T/S was partly mediated by the MPFC activation. Furthermore, the MPFC activation co-varied significantly with the FMRI signal in limbic areas and in areas that process self-relevant information. These results suggest that the MPFC may play an important role in mediating the relationship between depressive symptoms and clinical pain severity in RA, possibly by engaging brain areas important for affective and self-relevant processing.

This article will consider how physiological monitoring can be used both as an intrinsic part of an experiment, or for removing unwanted physiological signals from the FMRI time series. As functional MRI is used for a wide variety of applications beyond the identification of regions involved in a task, different sources of noise in the time series become important. The use of arterial spin labelling sequences, either in isolation or combined with BOLD imaging, means that temporal noise must be dealt with differently. Moreover, when these are combined with global cerebrovascular stimuli, such as respiratory challenges, the standard analysis tools must be employed with great care so as not to detrimentally distort the data. Acquiring and analysing physiological data is sometimes more art than science, and this article attempts to provide some insight into common techniques as well as advice on identifying and correcting some of the problems that may be encountered.

Background The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons. Methods An invitation to participate in an online survey was sent to all the email addresses in the members’ database of the British Orthopaedic Trainees Association (BOTA). Results All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial. Conclusions The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity. Electronic supplementary material The online version of this article (doi:10.1186/s12893-016-0142-5) contains supplementary material, which is available to authorized users.

Placebo surgery – often maligned as ‘sham surgery’ – is a tough sell to patients and to many clinicians. But could surgical research benefit from increased use of placebo control groups?

The therapeutic effects of centrally acting pharmaceuticals can manifest gradually and unreliably in patients, making the drug discovery process slow and expensive. Biological markers providing early evidence for clinical efficacy could help prioritize development of the more promising drug candidates. A potential source of such markers is functional magnetic resonance imaging (fMRI), a noninvasive imaging technique that can complement molecular imaging. fMRI has been used to characterize how drugs cause changes in brain activity. However, variation in study protocols and analysis techniques has made it difficult to identify consistent associations between subtle modulations of brain activity and clinical efficacy. We present and validate a general protocol for functional imaging–based assessment of drug activity in the central nervous system. The protocol uses machine learning methods and data from multiple published studies to identify reliable associations between drug-related activity modulations and drug efficacy, which can then be used to assess new data. A proof-of-concept version of this approach was developed and is shown here for analgesics (pain medication), and validated with eight separate studies of analgesic compounds. Our results show that the systematic integration of multistudy data permits the generalized inferences required for drug discovery. Multistudy integrative strategies of this type could help optimize the drug discovery and validation pipeline.

A magnetic resonance proton spectroscopic imaging (SI) technique was developed to measure regional brain temperatures in human subjects. The technique was validated in a homogeneous phantom and in four healthy volunteers. Simulations and calculations determined the theoretical measurement precision as approximately +/-0.3 degrees C for individual 1-ml voxels. In healthy volunteers, repeated measurements on individual voxels had an S.D. = 1.2 degrees C. In a clinical study, 40 patients with acute ischemic stroke were imaged within 26 h (mean, 10 h) of onset. Temperatures were highest in the region that appeared abnormal (i.e., ischemic) on diffusion-weighted imaging (DWI) compared with a normal-appearing brain. The mean temperature difference between the DWI "lesion" area and the "normal brain" was 0.17 degrees C [P < 10(-3); range, 2.45 degrees C (hotter)-2.17 degrees C (cooler)]. Noninvasive temperature measurement by SI has sufficient precision to be used in studies of pathophysiology in stroke and in other brain disorders and to monitor therapies.