Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Functional Outcome Following Stroke Thrombectomy in Clinical Practice.

Background and Purpose- Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods- Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0-2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results- Median age was 75 years (interquartile range, 64-82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10-19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions (P=0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05-1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03-1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08-1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15-1.39), alteplase use (OR, 1.49; 95% CI, 1.08-2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45-1.96). Conclusions- High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03356392.

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves.

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Continent-wide decoupling of Y-chromosomal genetic variation from language and geography in native South Americans.

Numerous studies of human populations in Europe and Asia have revealed a concordance between their extant genetic structure and the prevailing regional pattern of geography and language. For native South Americans, however, such evidence has been lacking so far. Therefore, we examined the relationship between Y-chromosomal genotype on the one hand, and male geographic origin and linguistic affiliation on the other, in the largest study of South American natives to date in terms of sampled individuals and populations. A total of 1,011 individuals, representing 50 tribal populations from 81 settlements, were genotyped for up to 17 short tandem repeat (STR) markers and 16 single nucleotide polymorphisms (Y-SNPs), the latter resolving phylogenetic lineages Q and C. Virtually no structure became apparent for the extant Y-chromosomal genetic variation of South American males that could sensibly be related to their inter-tribal geographic and linguistic relationships. This continent-wide decoupling is consistent with a rapid peopling of the continent followed by long periods of isolation in small groups. Furthermore, for the first time, we identified a distinct geographical cluster of Y-SNP lineages C-M217 (C3*) in South America. Such haplotypes are virtually absent from North and Central America, but occur at high frequency in Asia. Together with the locally confined Y-STR autocorrelation observed in our study as a whole, the available data therefore suggest a late introduction of C3* into South America no more than 6,000 years ago, perhaps via coastal or trans-Pacific routes. Extensive simulations revealed that the observed lack of haplogroup C3* among extant North and Central American natives is only compatible with low levels of migration between the ancestor populations of C3* carriers and non-carriers. In summary, our data highlight the fact that a pronounced correlation between genetic and geographic/cultural structure can only be expected under very specific conditions, most of which are likely not to have been met by the ancestors of native South Americans.

Endovascular treatment of primary M3 occlusion stroke in clinical practice: analysis of the German Stroke Registry.

BACKGROUND: Endovascular treatment (ET) options for acute stroke due to distal middle cerebral artery occlusions are rapidly evolving, but data on outcome and safety are sparse. We therefore performed an analysis of patients undergoing ET for primary M3 occlusions in routine clinical practice in a nationwide registry. METHODS: Patients enrolled between 01/20 and 12/21 in the prospective, multicenter German Stroke Registry-Endovascular Treatment (GSR-ET) were screened for mechanical thrombectomy performed for primary M3 occlusion. We analyzed neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), thrombectomy technique, successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3) and functional outcome as measured by the modified Rankin Scale (mRS) at discharge and 90 days. RESULTS: Out of 5574 patients, 11 patients (0.2%, median age 80 years, 54.5% female) underwent ET for primary M3 occlusion. All patients had pre-admission mRS ≤ 1, median NIHSS on admission was 8, and successful reperfusion was achieved in 6/11 patients (54.5%). While no vasospasm, dissection or perforation was reported, symptomatic intracranial hemorrhage occurred in 2 patients (18.2%). Favorable outcome (mRS ≤ 2) was achieved in 6/11 patients (54.5%) at 90-day follow-up. CONCLUSIONS: ET for primary M3 occlusions is rarely performed. While technically feasible, the procedure's potential benefits must be carefully weighed against its associated risks, including clinically relevant complications. Caution and further research is needed to optimize patient selection for this intervention. TRIAL REGISTRATION: GSR-ET; ClinicalTrials.gov Identifier: NCT03356392; Trial Registration Date: 11/29/2017.

Revascularization Techniques for Acute Basilar Artery Occlusion : Technical Considerations and Outcome in the Setting of Severe Posterior Circulation Steno-Occlusive Disease.

PURPOSE: To describe the clinical and radiological characteristics, frequency, technical aspects and outcome of endovascular treatment of acute basilar artery occlusion (ABO) in the setting of vertebrobasilar steno-occlusive disease. METHODS: Retrospective analysis of databases of two universitary stroke centers including all consecutive patients from January 2013 until May 2017 undergoing thrombectomy for a) acute stroke due to basilar artery occlusion and either significant basilar artery stenosis or vertebral artery stenosis/occlusion as well as b) presumed embolic basilar artery occlusions. Demographics, stroke characteristics, time metrics, recanalization results and outcome were recorded. Interventional strategies were evaluated concerning the thrombectomy technique, additional angioplasty, type of approach with respect to lesion pattern (ipsilateral to steno-occlusive VA lesion: dirty road or contralateral: clean road) and sequence of actions. RESULTS: Out of 157 patients treated for ABO 38 (24.2%) had associated significant vertebrobasilar steno-occlusive lesions. An underlying significant basilar artery stenosis was present in 23.7% and additionally significant steno-occlusive vertebral lesions were present in 81.5%. Thrombectomy was performed with primary aspiration in 15.8% and with stent-retrievers in 84.2%. Successful revascularization (TICI 2b-3) was achieved in 86.8%. In 52.6% additional stent angioplasty was performed, in 7.9% balloon angioplasty only. The clean road approach was used in 22.5% of cases, the dirty road in 77.4%. Final modified Rankin scale (mRS) was 0-2 in 6 patients (15.8%) and 3-5 in 32 (84.2%). The in-hospital mortality was 36.8%. There were no statistically significant differences in outcome compared to presumed cases of embolisms. CONCLUSION: Endovascular treatment of ABO with underlying significant vertebrobasilar steno-occlusive lesions is effective and reasonably safe. Specific procedural strategies apply depending on individual patient pathology and anatomy. Although high rates of recanalization can be achieved, outcomes tend to be poor.

Diagnostic and prognostic benefit of arterial spin labeling in subacute stroke.

BACKGROUND AND PURPOSE: Brain perfusion measurement in the subacute phase of stroke may support therapeutic decisions. We evaluated whether arterial spin labeling (ASL), a noninvasive perfusion imaging technique based on magnetic resonance imaging (MRI), adds diagnostic and prognostic benefit to diffusion-weighted imaging (DWI) in subacute stroke. METHODS: In a single-center imaging study, patients with DWI lesion(s) in the middle cerebral artery (MCA) territory were included. Onset to imaging time was ≤7 days and imaging included ASL and DWI sequences. Qualitative (standardized visual analysis) and quantitative perfusion analyses (region of interest analysis) were performed. Dichotomized early outcome (modified Rankin Scale [mRS] 0-2 vs. 3-6) was analyzed in two logistic regression models. Model 1 included DWI lesion volume, age, vascular pathology, admission NIHSS, and acute stroke treatment as covariates. Model 2 added the ASL-based perfusion pattern to Model 1. Receiver-operating-characteristic (ROC) and area-under-the-curve (AUC) were calculated for both models to assess their predictive power. The likelihood-ratio-test compared both models. RESULTS: Thirty-eight patients were included (median age 70 years, admission NIHSS 4, onset to imaging time 67 hr, discharge mRS 2). Qualitative perfusion analysis yielded additional diagnostic information in 84% of the patients. In the quantitative analysis, AUC for outcome prediction was 0.88 (95% CI 0.77-0.99) for Model 1 and 0.97 (95% CI 0.91-1.00) for Model 2. Inclusion of perfusion data significantly improved performance and outcome prediction (p = 0.002) of stroke imaging. CONCLUSIONS: In patients with subacute stroke, our study showed that adding perfusion imaging to structural imaging and clinical data significantly improved outcome prediction. This highlights the usefulness of ASL and noninvasive perfusion biomarkers in stroke diagnosis and management.

Systematic evaluation of stroke thrombectomy in clinical practice: The German Stroke Registry Endovascular Treatment.

BACKGROUND: Endovascular treatment has become standard of care for the treatment of acute ischemic stroke with large vessel occlusion. However, patients treated in clinical practice differ from the selected populations randomized in clinical trials. AIMS: The German Stroke Registry Endovascular Treatment (GSR-ET) aims at a systematic evaluation of outcome, safety, and process parameters of endovascular stroke treatment in standard of care in Germany. METHODS: The GSR-ET is an academic, independent, prospective, multicenter, observational registry study. Participating stroke centers from all over of Germany consecutively enroll patients transferred to the angiography suite with an intention to be treated with endovascular stroke treatment. Patients receive regular care. Data are collected as part of clinical routine. Baseline clinical and procedural information and clinical follow-up information after 90 days are recorded. Here, we present an analysis of baseline data of the first 1662 patients included in the GSR-ET. RESULTS: The registry was established in June 2015. By 31 December 2017, 1662 patients were enrolled in 23 active sites. Mean age was 72 ± 13 years, 50% were female, and median National Institutes of Health Stroke Scale on admission was 15 (IQR 10-19), 88% had anterior circulation occlusion. Median ASPECT score was 8 (IQR 7-10) prior to intervention. Fifty-nine percent of patients received intravenous thrombolysis prior to thrombectomy. Mean "onset-to-groin" time was 224 ± 176 min. CONCLUSIONS: Baseline characteristics of stroke patients undergoing thrombectomy in clinical practice differ from those in the randomized trials. The GSR-ET will provide valuable insights into practices of endovascular treatment in routine care of acute ischemic stroke. (GSR-ET ClinicalTrials.gov Identifier: NCT03356392.).

Correction for Susceptibility Distortions Increases the Performance of Arterial Spin Labeling in Patients with Cerebrovascular Disease.

BACKGROUND AND PURPOSE: Arterial spin labeling (ASL) is an MRI technique to measure cerebral blood flow (CBF) without the need of exogenous contrast agents and is thus a promising alternative to the clinical standard dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion imaging. Latest international guidelines encourage its application in the clinical setting. However, susceptibility-induced image distortions impair ASL with fast readout modules (eg Echo Planar Imaging, EPI; gradient and spin echo, GRASE). In the present study, we investigated the benefit of a distortion correction for ASL compared to DSC. METHODS: A pulsed ASL (PASL) sequence combined with a 3D-GRASE readout at multiple inflow times (multi-TI) was used and was corrected for susceptibility distortions using a FMRIB Software Library (FSL) implemented tool TOPUP. We performed qualitative (three expert raters) and quantitative (volume of interest [VOI]-based) comparisons of ASL and DSC imaging in 13 patients with chronic steno-occlusive disease. RESULTS: In the qualitative analysis, distortion correction of the images led to a strong increase in diagnostic precision of ASL compared to DSC in the anterior cerebral artery (ACA) perfusion territory, where the susceptibility artifact was most pronounced (specificity 8% vs. 75%). In the quantitative analysis, the correlation between ASL and DSC values increased for all perfusion territories with the best improvement for the ACA territory (for anterior, middle and posterior cerebral artery: ACA: rho -0.22 vs. 0.71; MCA: rho 0.58 vs. 0.76; PCA: rho 0.58 vs. 0.63). CONCLUSIONS: We showed that susceptibility distortion correction strongly improves the comparability of multi-TI ASL 3D-GRASE to DSC in steno-occlusive disease. We suggest it to be implemented in ASL postprocessing routines.

Hierarchical Y-SNP assay to study the hidden diversity and phylogenetic relationship of native populations in South America.

Studying the Y chromosomes of indigenous tribes of Ecuador revealed a lack of strategic SNP assays to examine the substructure of South American native populations. In most studies dealing with South American samples so far only the most common Y-SNP M3 of haplogroup Q was analyzed, because this is known to define a founder group in South America. Studies of SNPs ancestral to Q-M3 (Q1a3a) to confirm the results or the typing of Q subclades have often been neglected. For this reason we developed a SNaPshot assay, which allows first for a hierarchical testing of all main haplogroups occurring in South American populations and second for a detailed analysis of haplogroups Q and C thought having ancient Asian descent. We selected 16 SNPs from the YCC haplogroup tree and established two multiplexes. The first multiplex ("SA Major") includes 12 Y-SNPs defining the most frequent haplogroups occurring in South America (M42, M207, M242, M168, M3, M145, M174, M213, RPS4Y711, M45, P170, and M9). The second multiplex ("SA SpecQ") contains Y-SNPs of haplogroup Q, especially of the subclade Q-M3 (M19, M194, P292, M3, and M199). Within our Ecuadorian sample, haplogroup Q-M3 (xM19, M194, P292, and M199) was predominant, but we also found haplogroup E and R, which can be attributed to recent admixture. Moreover, we found four out of 65 samples, which were tested to be haplogroup C3* (C-M217) the modal haplogroup in Mongolians and widespread in indigenous populations of the Russian Far East as well as in Eastern Asia. This haplogroup is not known to be the result of recent admixture and has been found only one time before in South America. Since haplogroup C occurs in Asia and in North America (C3b or C-P39), we assume that these C-lineages are ancient as well. Therefore, we established a third multiplex ("SA SpecC"), which allows the further subtyping of haplogroup C, mainly of subclade C3 defined by the Y-SNP M217 (M407, M48, P53.1, M217, P62, RPS4Y711, M93, M86, and P39). Altogether, these three multiplexes cover the most frequent haplogroups in South America and allow for a maximal resolution of the Y-chromosomal SNP diversity in Amerindian population samples.

Motivational salience modulates hippocampal repetition suppression and functional connectivity in humans.

Repetition suppression (RS) is a rapid decrease of stimulus-related neuronal responses upon repeated presentation of a stimulus. Previous studies have demonstrated that negative emotional salience of stimuli enhances RS. It is, however, unclear how motivational salience of stimuli, such as reward-predicting value, influences RS for complex visual stimuli, and which brain regions might show differences in RS for reward-predicting and neutral stimuli. Here we investigated the influence of motivational salience on RS of complex scenes using event-related functional magnetic resonance imaging. Thirty young healthy volunteers performed a monetary incentive delay task with complex scenes (indoor vs. outdoor) serving as neutral or reward-predicting cue pictures. Each cue picture was presented three times. In line with previous findings, reward anticipation was associated with activations in the ventral striatum, midbrain, and orbitofrontal cortex (OFC). Stimulus repetition was associated with pronounced RS in ventral visual stream areas like the parahippocampal place area (PPA). An interaction of reward anticipation and RS was specifically observed in the anterior hippocampus, where a response decrease across repetitions was observed for the reward-predicting scenes only. Functional connectivity analysis further revealed specific activity-dependent connectivity increases of the hippocampus and the PPA and OFC. Our results suggest that hippocampal RS is sensitive to reward-predicting properties of stimuli and might therefore reflect a rapid, adaptive neural response mechanism for motivationally salient information.