Dipender Gill

Clinical Trials of Immunomodulation in Ischemic Stroke

Inflammatory mechanisms are currently considered as a prime target for stroke therapy. There is evidence from animal studies that immune signals and mediators can have both detrimental and beneficial effects in particular stages of the disease process. Moreover, several of these mechanisms are turned on with sufficient delay after ischemia onset to make them amenable to therapeutic intervention. Several clinical proof-of concept trials have investigated the efficacy of different immunomodulatory approaches in patients with stroke. Trials targeting the innate immune system have focused on reduction of microglial activation, inhibition of neutrophil migration, and interleukin-1 receptor blockade, suggesting that interleukin-1 receptor blockade may be a promising strategy. Studies aiming at halting T-cell migration have also been undertaken with controversial findings regarding prevention of infarct growth in neuroimaging studies. Consistently, recent proof-of-concept trials targeting lymphocytes with drugs such as natalizumab and fingolimod have yielded some promising results on clinical endpoints, but confirmation in larger trials is needed. At present, the understanding of the role of immune mechanisms in neurorepair and neurodegeneration is limited. Improving long-term brain function by mitigating prolonged neuroinflammation that was triggered by acute brain injury could be a strategy in addition to neuroprotection.

Dynamics of T cell responses after stroke.

T cells are integral to the pathophysiology of stroke. The initial inflammatory cascade leads to T cell migration, which results in deleterious and protective effects mediated through CD4(+), CD(8)+, γδ T cells and regulatory T cells, respectively. Cytokines are central to the T cell responses, with key roles established for TNF-α, IFN-γ, IL-17, IL-21 and IL-10. Through communication with the systemic immune system via neural and hormonal pathways, there is also transient immunosuppression after severe strokes. With time, the inflammatory process eventually transforms to one more conducive of repair and recovery, though some evidence also suggests ongoing chronic inflammation. The role of antigen-specific T cell responses requires further investigation. As our understanding develops, there is increasing scope to modulate the T cell response after stroke.

Mendelian randomization incorporating uncertainty about pleiotropy

Mendelian randomization (MR) requires strong assumptions about the genetic instruments, of which the most difficult to justify relate to pleiotropy. In a two-sample MR, different methods of analysis are available if we are able to assume, M1 : no pleiotropy (fixed effects meta-analysis), M2 : that there may be pleiotropy but that the average pleiotropic effect is zero (random effects meta-analysis), and M3 : that the average pleiotropic effect is nonzero (MR-Egger). In the latter 2 cases, we also require that the size of the pleiotropy is independent of the size of the effect on the exposure. Selecting one of these models without good reason would run the risk of misrepresenting the evidence for causality. The most conservative strategy would be to use M3 in all analyses as this makes the weakest assumptions, but such an analysis gives much less precise estimates and so should be avoided whenever stronger assumptions are credible. We consider the situation of a two-sample design when we are unsure which of these 3 pleiotropy models is appropriate. The analysis is placed within a Bayesian framework and Bayesian model averaging is used. We demonstrate that even large samples of the scale used in genome-wide meta-analysis may be insufficient to distinguish the pleiotropy models based on the data alone. Our simulations show that Bayesian model averaging provides a reasonable trade-off between bias and precision. Bayesian model averaging is recommended whenever there is uncertainty about the nature of the pleiotropy.

A Retrospective Cohort Study on the Use of Intravenous Thrombolysis in Stroke Mimics.

BACKGROUND The urgency of intravenous thrombolysis in acute ischemic stroke can lead to inadvertent thrombolysis of patients with nonstroke diagnoses (stroke mimics), increasing the risk of adverse events. The objectives of this study were to compare thrombolysed acute ischemic stroke and stroke mimic cases based on demographic factors, physiological parameters, radiological findings, and clinical presentation, and to evaluate the clinical implications of thrombolysing stroke mimics. METHODS A retrospective analysis of a single-center database of all thrombolysed strokes and mimics over a period greater than 3 years. Diagnoses were confirmed by expert consensus after a review of clinical factors and imaging. Intercohort variation was assessed using Wilcoxon rank-sum or Pearsons chi-square test. RESULTS The stroke mimic cohort tended to be younger (mean age 59.9 years versus 73.7 years, P < .001) and had a lower National Institutes of Health Stroke Score at presentation (mean 5.9 points versus 6.4 points, P < .01). However, the time taken from the onset of symptoms to delivery of thrombolytic drugs was longer in the mimic cohort (mean time 170 minutes versus 138 minutes, P < .01). Any differences in blood glucose (P = .07), time taken from hospital arrival to delivery of intravenous thrombolysis (P = .57), and blood pressure on admission (systolic, P = .09 and diastolic, P = .34) were not statistically significant. No adverse events were reported in the mimic cohort. CONCLUSION Despite similarities in clinical presentation, thrombolysed stroke mimics are of a different physiological and demographic population, and are associated with fewer adverse events compared with thrombolysed acute ischemic stroke patients.

The Effect of Iron Status on Risk of Coronary Artery Disease: A Mendelian Randomization Study

Objective— Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD). Approach and Results— A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88–1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91–0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73–0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01–1.16; P=0.034). Conclusions— This Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target.

A Fall in Systolic Blood Pressure 24 Hours after Thrombolysis for Acute Ischemic Stroke Is Associated with Early Neurological Recovery

BACKGROUND Outcomes are worse in patients who underwent thrombolysis for acute ischemic stroke (AIS) with persistent hypertension. The objective of this study is to investigate whether fall in systolic blood pressure (SBP) has any relationship with neurological outcome 24 hours after thrombolysis, after adjusting for potentially confounding factors. METHODS Retrospective analysis of a single-center database of consecutive thrombolysis cases for AIS. Multivariate regression analysis was used to explore the relationship between fall in SBP and reduction in National Institutes of Health Stroke Scale (NIHSS) score 24 hours after thrombolysis. Other potentially confounding predictor variables used in the model were SBP on thrombolysis, blood glucose level on thrombolysis, NIHSS score on thrombolysis, administration of antihypertensive medications, and the time to thrombolysis after symptom onset. RESULTS A fall in SBP 24 hours after thrombolysis is independently associated with greater improvement in NIHSS score 24 hours after thrombolysis (coefficient .051, 95% confidence interval .023-.078, P < .001). Thus, a reduction of 10 mmHg in SBP after 24 hours is associated with a .51 point reduction in the NIHSS score. CONCLUSIONS Restoration of SBP toward normal limits after thrombolysis for AIS is associated with greater early neurological improvement.

The role of the multidisciplinary team in decision making for vascular graft infection

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Age at menarche and adult body mass index: a Mendelian randomization study.

BackgroundPubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality.MethodsThe Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium.ResultsThere was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25–0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data.ConclusionMR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.

Resting right ventricular function is associated with exercise performance in PAH, but not in CTEPH

Aims To assess whether resting right ventricular (RV) function assessed by Global RV longitudinal strain (RVLS) and RV fractional area change (FAC) is associated with exercise performance in pulmonary arterial hypertension (PAH) and in chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results We prospectively recruited 46 consecutive patients with PAH and 42 patients with CTEPH who were referred for cardio-pulmonary exercise testing (CPET) and transthoracic echocardiography. Resting RV systolic function was assessed with RVLS and FAC. CPET parameters analyzed were percentage of predicted maximal oxygen consumption (VO2max) and the slope of ventilation against carbon dioxide production (VE/VCO2). Spearman correlation was performed between echocardiographic measurements and CPET measurements. In PAH, spearman correlation found an association between RVLS and VE/VCO2 (coefficient = 0.556, P < 0.001) and percentage predicted VO2max (coefficient = -0.393, P = 0.007), while FAC was associated with VE/VCO2 (coefficient = -0.481, P = 0.001) and percentage of predicted VO2max (coefficient = 0.356, P = 0.015). Conversely, in CTEPH, resting RV function was neither associated with percentage of predicted VO2max nor with VE/VCO2, whether assessed by RVLS or FAC. Conclusion In PAH, resting RV function as assessed by FAC or RVLS is associated with exercise performance and could therefore make a significant contribution to non-invasive assessment in PAH patients. This association is not found in CTEPH, suggesting a disconnection between resting RV function and exercise performance, with implications for the use of exercise measurements as a prognostic marker and clinical/research endpoint in CTEPH.

The effect of statins on severity of psoriasis: A systematic review.

Background: Psoriasis is becoming increasingly recognized as a chronic systemic inflammatory disease. Statins are generally well-tolerated drugs with pleiotropic effects including decreasing inflammation and may have the potential to reduce psoriasis severity. Aims: To examine whether oral statins reduce the severity of psoriatic skin disease. Methods: We searched MEDLINE, EMBASE and adapted for Google Scholar, Cochrane Central Register for Controlled Trials and Clinical trials.gov to January 6, 2016. We primarily examined randomized controlled trials that assessed the change in PASI score over a follow-up period of at least 8 weeks, for participants with an established diagnosis of psoriasis taking an oral statin versus placebo or other active treatment. Beyond this, we also examined other interventional studies that investigated the effect of statins on psoriasis severity using other designs. We extracted efficacy and adverse event data. The two study authors examined issues of study quality and study inclusion independently. Results: Three studies were identified which measured the change in psoriasis severity using PASI, comparing statin with placebo or standard therapy alone in a prospective, randomized study design; these showed conflicting results. However, among the excluded studies, majority of which used a single arm, non-placebo controlled study design, most showed an improvement in PASI scores after statin use. Limitations: Included studies were of limited sample size and quality. They were not amenable to pooled analysis. Conclusions: This review highlights the paucity of high quality, randomized, double-blinded, placebo-controlled trials investigating the effects of statins on psoriasis severity using clinically objective measures. There is insufficient evidence that the use of oral statins as an adjunctive therapy can reduce the severity of psoriasis.