Blood pressure determinants of cerebral white matter hyperintensities and microstructural injury: UK Biobank cohort study

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

Big cohort studies offer insights into preventable risk factors

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

White matter damage due to pulsatile versus steady blood pressure differs by vascular territory: a cross-sectional analysis of the UK biobank cohort study

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

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.</p

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

How do US orthopaedic surgeons view placebo-controlled surgical trials? A pilot online survey study

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

A meta-analysis of temporal changes of response in the placebo arm of surgical randomized controlled trials: an update

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.</p

68Ga-PSMA PET/CT and mpMRI for primary lymph node staging of intermediate to high-risk prostate cancer: a systematic review and meta-analysis of diagnostic test accuracy

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