Using arterial spin labelling to investigate spontaneous and evoked ongoing musculoskeletal pain

Clinical pain is difficult to study using standard Blood Oxy-genation 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

Quantitative assessment of barriers to the clinical development and adoption of cellular therapies:A pilot study

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community

The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union's Horizon 2020 programme

The QuinteT Recruitment Intervention supported five randomized trials to recruit to target: a mixed-methods evaluation

ObjectiveTo 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 SettingA mixed-methods study, comprising: a) before-and-after comparisons of recruitment rates and numbers of patients approached, and b) qualitative case studies, including documentary analysis and interviews with RCT investigators.ResultsFive UK-based publicly-funded RCTs were included in the evaluation. All recruited to target. RCT2 and RCT5 both received up-front pre-recruitment training before the intervention was applied. RCT2 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 post-QRI-action in RCTs 1,3, and 4. QRI-actions addressed issues with approaching eligible patients in RCTs 3 and 5, which both saw significant increases in patients approached. Trial investigators reported that the QRI had unearthed issues they had been unaware of, and reportedly changed their practices post QRI-action.ConclusionThere is promising evidence to suggest the QRI can support recruitment to difficult RCTs. This needs to be substantiated with future controlled evaluations

Low heart rate is associated with cerebral pulsatility after TIA or minor stroke

Objective Beta-blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. Methods Patients 4–6 weeks after TIA or non-disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat-to-beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA-PI) are reported as beta-coefficients from general linear models for each individual. Results Across 759 patients, average MCA-PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA-PI per 10 bpm/mmHg: −0.02, −0.04, 0.03, all p  70 + HR  65: −0.081 vs −0.024, interaction p  70 + severe vs age  Interpretation Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target

Consistencies and differences in intermediate physiological phenotypes of vascular ageing between ischaemic stroke aetiologies

Objective: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. Methods: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. Results: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. Conclusions: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group

Placebo's invisible brother: a restricted scoping review of the biomedical literature on the nocebo effect

Placebos and their beneficial clinical and psychological effects are well-researched, but nocebo effects receive far less attention, despite being highly undesirable. The aim of this restricted scoping review was to examine how nocebo effects are represented in the biomedical literature and to identify the trends and gaps in existing knowledge. After searching 5 biomedical databases and 2 clinical trials registries (from their inception to December 23, 2020) for articles on nocebo effects or negative placebo effects, 1161 eligible publications were identified. The 2 main publication types were nonsystematic reviews (37.7%) and primary research studies (35.6%); only 85 publications (7.3%) were systematic reviews and meta-analyses. The nonsystematic reviews, many of them heavily opinion-based, may contribute to the amplification of narratives, attitudes, and beliefs about nocebo effects that do not objectively reflect the primary research. The primary research articles often used nocebo effects to explain results, rather than as the primary phenomenon under investigation. Most publications were concerned with both positive and negative placebo effects, rather than just nocebo effects. Over half of the abstracts were in the field of neurology, psychiatry, psychology, or neuroscience (52.8%). The nocebo effect was most frequently investigated in the context of pain. Studies were almost exclusively in adults and more often in healthy participants than in patients. In conclusion, in the biomedical literature, there is an overabundance of nonsystematic reviews and expert opinions and a lack of primary research and high-quality systematic reviews and meta-analyses specifically dealing with nocebo effects

Learning to identify CNS drug action and efficacy using multistudy fMRI data

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

The implementation of novel collaborative structures for the identification and resolution of barriers to pluripotent stem cell translation.

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