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 is that they provide important indicators of treatment efficacy not captured by objective markers or clinical assessments.1 6 They may be used as ‘red flags’ during the assessment of acute symptoms and help to monitor response to treatment, for example, the efficacy of analgesia, especially if they are collected in real time.2 Moreover, well-developed PROMs for a specific condition may measure treatment effects on many domains, which is useful because treatment may have a different effect on disease-specific outcomes, health status and quality of life.9 Finally, reporting PROMs improves communication between the patient and the care provider and, in turn, increases patient’s satisfaction with treatment2 and, subsequently, helps with adherence to the treatment itself and with patient retention.10 Considerations for the use of PROMs Potential limitations and biases associated with PROMs are rarely acknowledged,2 3 5 11 although both EMA and FDA recognise that PROMs may not be suitable as primary outcomes in open-label settings and that they should be supported by objective or functional outcomes.1 6 By the nature of being subjective, PROMs may be affected by internal factors, such as mood, expectations, time and sentiments, and external factors such as treatment context, interactions with the healthcare providers and patients’ socioeconomic situation, which leads to fluctuations in the outcomes. ...patients are not necessarily able to identify an improvement in their own health. ...due to variability, PROMs measurements are often categorised, which reduces reliability and decreases power.17 Strategies to improve the use of PROMs In open-label settings, patients are likely to exaggerate the treatment effect, especially if the treatment is invasive.18 18 19 Blinding of patients reduces reporting bias as well as a risk of unbalanced attrition or cointerventions,18 and blinding of doctors or researches reduces observer’s and detection bias; however, biases related to unblinded patients tend to be larger than those caused by unblinded assessors.19 20 When blinding is not possible, PROMs collection should be combined with functional, imaging and biochemical biomarkers adding an element of objectivity.1 6 The treatment effect should improve patients’ satisfaction and surpass the placebo effect; therefore, when it is important to assess the magnitude of improvement or harms associated with an active intervention, a placebo-controlled randomised controlled trial (RCT) may be necessary.21 The variability of PROMs can be mitigated by collecting measurements at multiple time points to assess the trajectories of symptoms’ progression and recovery. ...PROMs should be used in conjunction with objective outcomes, especially when assessment by blinded clinicians or researchers is not possible.
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.
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.
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.
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.
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.
Abstract
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 (<3/10 on the numerical ratings scale NRS) at six months following TKA and 15 people with HIGH_PAIN (≥3/10 on the NRS) were recruited into the study.
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.
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 < 0.001), with HR particularly associated with low end‐diastolic cerebral velocity (0.86, p = 0.014). Beat‐to‐beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat‐to‐beat cerebral pulsatility (average ∆MCA‐PI vs HR/DBP/SBP unadjusted: −0.062, −0.052, 0.0092; adjusted for concurrent BP: −0.039, −0.11, 0.041). The beat‐to‐beat association between HR and MCA‐PI increased with age, beta‐blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: −0.081 vs −0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: −0.087 vs −0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA‐PI.
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. ANN NEUROL 2022;92:909–920
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.
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.
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.
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 (β
= 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 (β
= 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 (β
= 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.
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.
Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with ...small vessel disease.
We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated.
Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years SD 9·9) and 26 with CADASIL (53·1 years 7·0) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10–4%/mm Hg SE 20·1; 95% CI –37·6 to 41·2 for amlodipine; 16·7 × 10–4%/mm Hg 20·0; –22·3 to 55·8 for losartan; –7·1 × 10–4%/mm Hg 19·6; –45·5 to 31·1 for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10–4%/mm Hg SE 27·5; 95% CI –38·3 to 69·7 for amlodipine; 19·4 × 10–4%/mm Hg 27·9; –35·3 to 74·2 for losartan; –23·9 × 10–4%/mm Hg 27·5; –77·7 to 30·0 for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (–39·6 × 10–4%/mm Hg 95% CI –72·5 to –6·6; p=0·019) and with losartan compared with atenolol (–43·3 × 10–4%/mm Hg –74·3 to –12·3; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake.
4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.
EU Horizon 2020 programme.
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