American Heart Association

prognosis

The PHASES score for prediction of intracranial aneurysm growth

The authors of this study make the argument that for most small aneurysms in the anterior circulation, the predicted risk of rupture is much smaller than the risk of treatment complications, and therefore many of these small aneurysms are left untreated. However, a small proportion of these aneurysms do rupture and because these aneurysms by far outnumber other aneurysms, most instances of aneurysmal subarachnoid hemorrhage come from small aneurysms in the anterior circulation. Thus, the need for a better risk prediction model is required. The PHASES score is a model that provides absolute risks of rupture for aneurysms based on six easily retrievable factors which include population, hypertension, age, size of aneurysm, earlier SAH from another aneurysm, site of aneurysm. The score was utilized in this study to see if it is a predictor of aneurysm growth.
 

The authors analyzed a multicenter cohort of patients with unruptured intracranial aneurysms and follow-up imaging with computed tomography angiography or magnetic resonance angiography. They included 557 patients with 734 unruptured aneurysms. Eighty-nine (12%) aneurysms in 87 patients showed growth during a median follow-up of 2.7 patient-years (range 0.5-10.8). Using this cohort, they performed univariable and multivariable Cox regression analyses for the predictors of the PHASES score at baseline, with aneurysm growth as outcome. Per point increase in PHASES score hazard ratio (HR) for aneurysm growth was 1.32 (95% CI: 1.22-1.43). With the lowest quartile of the PHASES score (0-1) as reference, HRs for the second [PHASES 2-3] 1.07 (95% CI: 0.49-2.32), the third [PHASES 4] 2.29 (95% CI: 1.05-4.95), and the fourth quartile [PHASES 5-14] 2.85 (95% CI: 1.43-5.67).
 
It was concluded that this study shows that the PHASES risk score, which provides 5-year absolute risks of aneurysmal rupture, can also be used to identify aneurysms with a high relative risk of aneurysm growth. Despite the strengths of the study, while the PHASES score can be utilized as another surrogate marker for identification of aneurysms that have a higher risk of growth and also an aneurysms risk for rupture, it should be utilized with caution. This score will require further confirmation of its validity before it is implemented on a larger scale as aneurysms should not needlessly be treated give the risks and complications associated with the procedure.
By |March 24th, 2015|prognosis|Comments Off on The PHASES score for prediction of intracranial aneurysm growth
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What results in neurological deterioration after spontaneous intracerebral hemorrhage?

Prachi Mehndiratta, MD

Lord AS, Gilmore E, Choi HA, and Mayer SA, on behalf of VISTA-ICH Collaboration. Time Course and Predictors of Neurological Deterioration After Intracerebral Hemorrhage. Stroke. 2015


Spontaneous Intracerebral Hemorrhage (sICH) can be serious and life threatening based on hemorrhage and clinical characteristics. If you remember the Hemphill ICH score, you can predict 30 day mortality from ICH based on a combination of clinical and imaging characteristics. We also know from prior studies that hematomas often snowball and increase in size in the first 24 hours and our best chance of good recovery lies in halting hematoma growth. The authors of this study aim to identify the predictors of neurological deterioration after a sICH. They enrolled patients into a retrospective cohort from the VISTA database and attempted to identify clinical and radiological features associated with a pre-defined neurological deterioration at various points in time. These patients were enrolled in the placebo arms of prospective, randomized trials of acute treatment for ICH and baseline as well as follow up CT scans, rigorous physical exam data and a 3 month mRS score. 



Neurological deterioration (ND) was defined as hyper-acute ( <1 hour), acute (1-24 hours), sub-acute (1-3 days) and delayed (3-15 days). Univariate and multivariate analyses were performed to identify demographic, clinical and radiographic factors that were associated with deterioration in each subgroup. Chi-square, Fisher’s exact test, Mann-Whitney-U test and logistic regression were used for analysis. A total of 376 patients were included in the cohort and ND occurred in 176 patients, 170 at discrete pre specified time points and in 6 patients gradually over multiple time periods. The predictors of ND were intuitive – patients with hyperacute and acute ND had lower GCS, higher NIHSS, larger hematoma volumes and presence of IVH. Patients with subacute ND were similar to those with acute ND but in addition had higher rates of fever and increased IVH blood volumes. Multivariate analysis revealed that delayed ND was associated with older age, higher troponin levels and infection in the 3-15 day period.

The study was well done and well-intended but does it really affect my practice? I don’t think so. I know that patients with certain ICH clinical and radiographic characteristics can get worse and as a stroke physician I need to make sure their hemorrhage volume does not increase, provide them the best supportive neurocritical care and make sure they don’t get infected in order to improve their chances for survival from an illness that already carries a very high morbidity and mortality.

By |February 23rd, 2015|prognosis|1 Comment
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No relation of lipid lowering agents to hematoma growth

Rajbeer Singh Sangha, MD

Priglinger M, Arima H, Anderson C, and Krause M. No Relationship of Lipid-Lowering Agents to Hematoma Growth: Pooled Analysisof the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials Studies. Stroke. 2015

Controversy persists over whether statins increase the risk of intracerebral hemorrhage (ICH). A recent systematic overview of randomized trials found no association of statins and the risk of ICH, but less evidence exists for populations with high rates of ICH. Statins do not appear to increase risks of poor functional outcomes in ICH, but no study has examined their association with hematoma growth which may be promoted by ancillary mechanisms. Previous studies have was shown that statins increase fibrinolytic and/or decrease pro-thrombotic mechanisms in vitro. In aortic endothelial cells, statins increase mRNA and enzymatic activity of tissue type plasminogen activator (tPA) (Essig et al., 1998), and decrease mRNA and activity of plasminogen activator inhibitor-type1 (PAI-1) (Bourcier and Libby, 2000). These mechanisms suggest that statins may lead to inhibition of platelet aggregation and thrombogenesis and thereby postulated to affect hematoma growth. The authors of this study examined associations of lipid lowering therapy, hematoma growth and clinical outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT).


The authors analyzed the data from the INTERACT trials (1 and 2) which were international, multicenter, open, blinded endpoint, randomized controlled trials with a common protocol that collectively compromised 3243 patients with spontaneous ICH (<6 hours of onset) and elevated systolic blood pressure (SBP 150-220mmHg) randomly allocated to receive intensive or guideline-based BP management. Out of 3184 participants included in the analyses, 204 (6.5%) were on lipid lowering therapy at the time of ICH. 90 day clinical outcomes were not significantly different after adjustment for confounding variables including region and age. In the CT substudy, analysis of 24 hour hematoma growth was greater in 124 patients (9%) with, compared to those without, prior lipid lowering therapy. However, this association was not significant between the two groups (9.2ml vs 6.8ml, p<0.13), after adjustment for prior antithrombotic therapy. This study found no difference in clinical outcomes, initial ICH volume, or 24 hour hematoma volume growth between patients with and without lipid lowering therapy at the time of acute ICH.

After multiple studies, analyses and debates, the evidence seems to be pointing towards the safe utilization of statins during acute ICH. While many of these studies are underpowered to determine a significant effect of statins, the safety profile continues to be established in favor of statin use. It seems that until no large multicenter center does not analyze the effect statins have on ICH we won’t have a conclusive answer and the “controversy” will continue to rage on. Of course, there is the very real possibility that statin use will be limited in the next five years as lipid lowering agents will most likely be comprised of a new class of drugs.

References:
1. Bourcier T, Libby P. HMG-CoA reductase inhibitors reduces plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000;20:556–562
2. Essig M, Nguyen G, Prie D, Escoubet B, Sraer J-D, Friedlander G. 3-hydroxy-3-methylglutarylCoenzyme A reductase inhiitors increase fibrinolytic activity in rat aortic endothelial cells. Circ Res 1998;83:683–690.

By |February 17th, 2015|prognosis|Comments Off on No relation of lipid lowering agents to hematoma growth
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Biomarkers Predict Death After Stroke

Rizwan Kalani, MD

Greisenegger S, Segal HC, Burgess AI, Poole DL,  Mehta Z, and Rothwell PM. Biomarkers and Mortality After Transient Ischemic Attack and Minor IschemicStroke: Population-Based Study. Stroke. 2015

Premature death after stroke or TIA is more often a consequence of cardiac disease or malignancy than the cerebrovascular event itself. Prior studies evaluating various serologic biomarkers for predicting recurrent vascular events or death after stroke/TIA have shown mixed results. Greisenegger et al evaluated the association of several biomarkers with all-cause mortality (particularly cardiac or cancer death) in those with minor stroke or TIA.


The cohort studied came from an ongoing population based-study of vascular disease incidence and outcomes in Oxfordshire, UK (Oxford Vascular Study). TIA was defined according to the WHO definition (<24 hours of focal neurological deficit suspected to be of vascular cause – not imaging-based definition that excludes tissue injury) and minor stroke included those with NIHSS<3. Patient death was classified into vascular (stroke, cardiac, etc.) and non-vascular (cancer, other systems) causes. The panel of biomarkers collected are implicated in 1. the inflammatory response – IL-6, CRP, neutrophil-gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor-1 (sTNFR-1); 2. thrombosis – thrombomodulin (TM), fibrinogen, P-selectin, D-dimer, von Willebrand factor (vWF), protein-Z; 3. cardiac function – nt-proBNP; 4. cardiac/neuronal injury – neuron-specific enolase (NSE), heart-type fatty acid binding protein (HFABP); and 5. neural regeneration – BDNF.

929 patients with TIA (47%) and minor stroke (53%) were enrolled. The median age was 74 years and 51% were female. Biomarkers were drawn on average 5 days after the cerebrovascular event; the median follow-up of patients was 6.4 years. 39% (361/929) of patients died during the follow-up period – 151 of vascular cause, 184 non-vascular cause, and 26 unclear etiology. None of the biomarkers correlated with recurrent non-fatal stroke or MI. sTNFR-1, NGAL, CRP, IL-6, vWF, nt-proBNP, and hFABP were predictive of all-cause mortality after adjusting for demographics, risk factors, and prior medical therapy. The strongest associations were for sTNFR-1 (HR 1.45), nt-proBNP (HR 1.44), and hFABP (HR 1.37). sTNFR-1, NGAL, vWF, nt-proBNP, and hFABP were predictive of vascular death in multivariate analysis with the strongest association detected for nt-proBNP (HR 1.8). Among those, all but NGAL were predictive of cardiac death. Nt-proBNP was strongest predictor of stroke-related death. IL-6, CRP, NGAL, sTNFR-1, and hFABP were predictive of non-vascular death. The strongest associations were for hFABP (HR 1.5) and sTNFR-1 (HR 1.47); these two were also predictive of cancer-related death (hFABP HR 1.61, sTNFR-1 HR 1.41). Taken together, sTNFR-1, vWF, hFABP, and nt-proBNP added more prognostic information in comparison to outcome prediction models based on clinical risk factors. These four markers remained predictive of all-cause mortality at 2, 3, and 5 year follow-up.

This study demonstrates that biomarkers related to the inflammatory response, cardiac function, cardiac/neuronal injury, and thrombosis are independent predictors of death in patients with minor stroke or TIA. Those with highest predictive value were sTNFR-1, vWF, nt-proBNP and hFABP. The value of nt-proBNP was shown to be specifically predictive of vascular death and may assist in guiding further cardiac evaluation after stroke. hFABP may be of value for identifying occult malignancy after cerebrovascular ischemia, but this needs to be evaluated in independent cohorts. Future studies will have to validate this and assess the utility of incorporating these biomarkers in clinical care.

By |February 10th, 2015|prognosis|1 Comment
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Location, Location, Location: Distance from Carotid Terminus to MCA Clot Predicts Outcome

Mark N. Rubin, MD

Friedrich B, Gawlitza M, Schob S, Hobohm C, Raviolo M, Hoffmann KT, and Lobsien D, Distance to Thrombus in Acute Middle Cerebral Artery Occlusion: A Predictor of Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke. Stroke. 2015


It is well known to strokologists that patients with acute ischemic stroke from proximal occlusions tend to fare poorly as compared to those with distal occlusions. Several prospective and retrospective observational studies have confirmed this relationship. What has been lacking, however, is precision in the definition of “proximal occlusion,” as seen with the heterogeneity of definitions across trials and observational studies.



This interesting CTA-based imaging study sought to rigidly stratify occlusion location by distance from a single anatomical landmark: the middle of the “carotid T.” In a standardized fashion, the investigators looked back at CTA studies from 136 patients who received IV tPA and measured from the midpoint of the distal ICA to the proximal end of a clot and compared that distance to 7-day NIHSS and 90-day mRS. Overall, the main finding was the distance from the carotid T to the clot was an independent predictor of outcome, even when controlling for clot length. There was an exponential decline in likelihood of good outcome (mRS < or = 2) with distance to thrombus of <16mm. Short distance to thrombus also predicted long thrombus length as compared to more distal occlusions.

In addition to assisting in the definition of proximal occlusions with discrete measurements and a practical anatomical landmark for standardization, this investigation also suggests that perhaps we should pay more attention to clot location and length in our treatment trials and natural history studies, as evidence mounts that these data are quite relevant.

By |February 9th, 2015|prognosis|Comments Off on Location, Location, Location: Distance from Carotid Terminus to MCA Clot Predicts Outcome
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Responsiveness after Hemorrhagic Stroke – Role of the Frontal Networks

Rizwan Kalani, MD

Mikell CB, Banks GP, Frey HP, Youngerman BE, Nelp TB, Karas PJ, et al. Frontal Networks Associated With Command Following After Hemorrhagic Stroke. Stroke. 2014

We often assess level of arousal by a patient’s ability to follow commands. In this study, Mikell et al evaluated which brain structures are necessary to follow commands in the setting of acute intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) using a multimodality approach – a combination of structural and functional MRI (fMRI) as well as continuous EEG monitoring.


Data from 25 patients with spontaneous ICH or SAH that completed all components of the multi-modality testing were analyzed from a prospective, single-center database. 9 patients (36%) were unresponsive (unable to follow simple, 1-step commands) and 16 were awake at time of testing. Structural injury to the pons, midbrain, and thalamus was initially evaluated (by lesion volume quantification) using structural MRI. Resting state fMRI was then used to identify which brain networks were disrupted in the unresponsive patients compared to those who were awake. The relationship between the default mode network (DMN – the brain regions active when a person is awake and at rest) and the task-positive network (TPN – areas responding to attention-demanding tasks) were evaluated. Lastly, continuous EEG was used to confirm changes in functional connectivity seen.

There was no significant difference between the hemorrhage sizes of the unresponsive and awake patients. 6 functional networks were impaired in unresponsive patients by fMRI – these were located in the premotor, dorsal anterior cingulate, and supplementary motor areas. Connectivity between the DMN and right orbitofrontal cortex was decreased in unresponsive patients. Interestingly, new connections between the TPN and DMN were seen in unresponsive patients that were not seen in those who were awake. These findings were supported by EEG coherence data.

This manuscript suggests that disruption of frontal network connectivity (instead of the actual structural injury) accounts for unresponsiveness in the setting of ICH/SAH. It supports the idea that altered connectivity to (rather than within) the DMN is lost in an unresponsive state. Future studies will need to evaluate the mechanisms by which these network connectivity changes occur and how each individual network involved affects consciousness. The principal limitations of this study are the small number of patients included and inability to evaluate the effect of intracranial pressure on the findings.

By |December 10th, 2014|prognosis|Comments Off on Responsiveness after Hemorrhagic Stroke – Role of the Frontal Networks
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Ischemia on CT is Predictive of Recurrent Stroke within 90 days for TIA/non-disabling Stroke Patients

Duy Le, MD

Wasserman JK, Perry JJ, Sivilotti MLA, Sutherland J, Worster A, Émond M, et al. Computed Tomography Identifies Patients at High Risk for Stroke After Transient Ischemic Attack/Nondisabling Stroke: Prospective, Multicenter Cohort Study. Stroke. 2014

Wasserman et al evaluate the predictive value of CT findings and risk of stroke. Specifically, they evaluate 2028 patients who presented to the hospital within 48 hours of symptoms, who had either a TIA or non-disabling stroke, receiving a scan within 24 hours. Head CT’s were evaluated by local neuro-radiologist as either being present or absent for evidence of acute ischemia, chronic ischemia and microagniopathy. Do these aforementioned patients with recent TIA or non-disabling stroke predict a higher likelihood of stroke in the forthcoming days? Wasserman et al answer: Yes! Stroke risk at 90 days was greater if baseline CT showed acute ischemia alone (10.6%; p = 0.002), acute + chronic ischemia (17.4%; p = 0.007), acute ischemia + microangiopathy (17.6%; p=0.019), or acute + chronic + microangiopathy (25.0%; p =0.029). The average age of patient’s was 67.9 +/- 14.5. 


Limitations of this study include the fact that only CT’s were used. CT’s are known to be less sensitive at detecting ischemia as compared to MRI’s. However some may argue that this models real world practical evaluation of strokes in the acute and early sub-acute strokes. A second limitation is that there was no distinction made between symptomatic and non-symptomatic acute lesions on head CT. Although acute ischemia seen on imaging in those with TIA symptoms or non-disabling stroke was shown to have higher risk of repeat ischemic event, from the data, we are unable to determine if patient’s new event was secondary to a new stroke or progression of the original stroke. This potentially may skew the data.

This study nonetheless, does show that imaging is useful in predicting future stroke in 90 days. Some may argue that imaging used as single parameter in this clinical setting may not be too useful. However, if used in conjunction with the ABCD2 score (as is seen in the new ABCD2I score), there may be clinical application. As with the ABCD2 score which stratifies risk of an immediate stroke, using imaging as a stroke risk marker will act to dictate management. Should a patient be admitted for expedited stroke work up inpatient, or can the patient have an outpatient work up? For those who mull over this question, imaging can act as an additional data point. It does seem intuitive otherwise that having a prior stroke would increase the risk of a subsequent stroke. However, now we can quantify that risk within 90 days and specify that to imaging findings.

By |December 5th, 2014|prognosis|Comments Off on Ischemia on CT is Predictive of Recurrent Stroke within 90 days for TIA/non-disabling Stroke Patients
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Back Again: Hospital Readmissions after Stroke

Mark L. McAllister, MD


Evaluating an acute ischemic stroke patient in the inpatient setting, our concerns are often focused on determination of stroke etiology and secondary prevention measures, evaluating and treating early complications, and preparing patients for rehabilitation. What happens after the patient leaves the hospital is often a secondary concern. Readmission to the hospital is a common and deleterious outcome for many stroke patients.


The authors here investigated the rates of readmission among stroke patients in Dijon, France. Of 519 patients with first time stroke who survived initial hospitalization, 32% had a hospitalization in the first year after their discharge. The leading cause of admission was neurologic complaints, with stroke or TIA being the most frequent in that category. Unsurprisingly, patients who were older, had more comorbidities, and more severe initial strokes were most likely to have readmission in the year following stroke.

What is not clear in this study is what proportion of hospitalizations were due to preventable causes, and especially causes that were preventable based on actions taking place during the acute hospitalization for stroke. Readmission adversely affects patients’ general level of health and independence, emphasizing the need to minimize preventable readmissions. Finally, the correlation with initial stroke severity and rehospitalization further underscores the need for aggressive primary prevention measures in stroke to avoid these patients’ initial hospitalization.  

By |November 25th, 2014|prognosis|Comments Off on Back Again: Hospital Readmissions after Stroke
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Broken Cookie Cutter: The Natural History of Unruptured Intradural Fusiform Aneurysms

Vikas Pandey, MD


Fusiform intracranial aneurysms are an entity that are not well studied, mainly due to the fact that fusiform aneursysms are rarer compared to saccular ones. The concept that the etiology of fusiform aneurysms is multifold leads to questions whether the approach to treat these types of aneuryms should be different based on specific aneurysmal characteristics as well as parts of the patient’s medical history. The authors headed by the interventional neuroradiology group from Toronto challenged the idea that treating fusiform intradural aneurysms carries a poor prognosis, an idea that has been ingrained due to poor prognosis of previously studied populations of veretebrobasilar fusiform aneurysms, and proposed that the natural histories of the different etiologies of fusiform aneurysms may be different.



The author conducted a retrospective study of patients seen between a 13 year period at Toronto Western Hospital cerebrovascular clinic and looked at 121 patients with unruptured intradural aneurysmal dilatation of >50% of the vessel wall circumference. Patients that were excluded were those with diameter >2.5 cm (these have a known poor natural history) and those with entirely extradural aneurysms. The aneurysms were categorized into those that were related to atherosclerosis and those that weren’t based on imaging criteria such as presence of eccentric, calcified plaques present within the aneurysms, as well as with supporting criteria based on risk factors for atherosclerosis (25 out of 121 put into this group). The groups were followed for 193 and 97 person-years for the non-atherosclerotic and atherosclerotic groups respectively. Results showed that the mortality in the atherosclerotic group was higher (5.2%/year vs 0.51%/year) and they had a higher aneurysm progression risk (12%/year vs 1.6%/year compared to the non-atherosclerotic counterparts.

The results provide an interesting dimension to treatment algorithms for fusiform aneurysms. The common sense risk factors such as a size and symptomatic presentation are not to be overshadowed, but looking into aspects of the pathophysiology of aneurysms which may appear similar on initial radiographic studies is an idea that should be applied to all areas of medicine. The authors bring up the very valid point that atherosclerotic aneurysms and non-atherosclerotic fusiform aneurysms should be thought of as entirely different disease entities. “Cookie cutter” medicine is very hard, especially in the field of stroke neurology and the authors provide us with an excellent example of this.

@DrVikasNeuro

By |September 30th, 2014|prognosis|Comments Off on Broken Cookie Cutter: The Natural History of Unruptured Intradural Fusiform Aneurysms
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Time is Brain, again and again!

Chirantan Banerjee, MD

Muchada M, Rodriguez-Luna D, Pagola J, Flores A, Sanjuan E, Meler P, et al. Impact of Time to Treatment on Tissue-Type Plasminogen Activator–Induced Recanalization in Acute Ischemic Stroke. Stroke. 2014

The importance of time in hyperacute stroke care cannot be emphasized enough. In the NINDS tPA trial, the odds of a good functional outcome with IV tPA dropped from 2.6 if given between 0 – 90 min to 1.2 when given 271 – 360 min. Similarly, the NNT increased from 4.5 to 21.4. In the IMS-III trial, one of the major messages that emerged from the data was again that delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. With every step we take towards advancing acute stroke care, the importance of time to reperfusion keeps coming up again and again.




Now that the effect of time on functional outcome has been established, one interesting question that I have always had is that does delay in tPA delivery fail to improve outcomes with time because the brain tissue is not salvageable anymore, or that its efficacy to recanalize suffers as the clot matures, or a combination of the two. Muchada et al in the current issue of Stroke aimed to assess the influence of time on tPA induced recanalization in acute stroke patients. 508 consecutive acute stroke patients with proven MCA occlusions by TCD and who received IV tPA up to 4.5 hours, as well as ~6% who received tPA between 4.5 – 6 hours (selected by penumbral imaging) were included. Mean time to treatment was 171 min over the 7 year study period. TCD was repeated 1 hour post tPA. Any improvement in the TCD signal was considered to indicate recanalization. There was no linear association between time-to-treatment and recanalization. However, when converted to sequential 30 min time-to-treatment windows, as well as when dichotomized to <=270 min or >270 min, recanalization was seen to decrease with time. Several findings in the study corroborate with prior data. 

Overall recanalization rate of 36% is consistent with 30-40% previously reported. Also, higher NIHSS score, hyperglycemia, older age and female sex were again seen to decrease chance of recanalization.  Proximal MCA occlusions had a trend towards lower recanalization rate, especially after the first 90 min, in synergy with previous reports.  Distal occlusions had a recanalization rate ~30% regardless of time. The main limitation of the study is the measurement bias associated with use of TCD to assess vessel status. Also, the fact that only 6% patients received tPA >270 minutes affects the distribution of data. Some variables such as pre-treatment ASPECTS which have been previously shown to affect recanalization status were not included in the model.
This study again emphasizes the importance of time in acute stroke care, and finds poor recanalization outcomes beyond 270 min for proximal MCA occlusions. The authors argue that IV thrombolysis may be insufficient beyond this window, and more aggressive therapies should be explored. The critical question is, would it even matter if you do recanalize the occluded vessel at that point, or has the ship sunk already! 
By |August 26th, 2014|prognosis|Comments Off on Time is Brain, again and again!
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