Deletion of the entire AZFc locus on the human Y chromosome leads to male infertility. The functional roles of the individual gene families mapped to AZFc are, however, still poorly understood, since the analysis of the region is complicated by its repeated structure. We have therefore used single-nucleotide variants (SNVs) across approximately 3 Mb of the AZFc sequence to identify 17 AZFc haplotypes and have examined them for deletion of individual AZFc gene copies. We found five individuals who lacked SNVs from a large segment of DNA containing the DAZ3/DAZ4 and BPY2.2/BPY2.3 gene doublets in distal AZFc. Southern blot analyses showed that the lack of these SNVs was due to deletion of the underlying DNA segment. Typing 118 binary Y markers showed that all five individuals belonged to Y haplogroup N, and 15 of 15 independently ascertained men in haplogroup N carried a similar deletion. Haplogroup N is known to be common and widespread in Europe and Asia, and there is no indication of reduced fertility in men with this Y chromosome. We therefore conclude that a common variant of the human Y chromosome lacks the DAZ3/DAZ4 and BPY2.2/BPY2.3 doublets in distal AZFc and thus that these genes cannot be required for male fertility; the gene content of the AZFc locus is likely to be genetically redundant. Furthermore, the observed deletions cannot be derived from the GenBank reference sequence by a single recombination event; an origin by homologous recombination from such a sequence organization must be preceded by an inversion event. These data confirm the expectation that the human Y chromosome sequence and gene complement may differ substantially between individuals and more variations are to be expected in different Y chromosomal haplogroups.

Endovascular thrombectomy (EVT) is well established as a highly effective treatment for acute ischemic stroke (AIS) due to proximal, large vessel occlusions (PLVOs). With iterative further advances in catheter technology, distal, medium vessel occlusions (DMVOs) are now emerging as a promising next potential EVT frontier. This consensus statement integrates recent epidemiological, anatomic, clinical, imaging, and therapeutic research on DMVO-AIS and provides a framework for further studies. DMVOs cause 25% to 40% of AISs, arising as primary thromboemboli and as unintended consequences of EVT performed for PLVOs, including emboli to new territories (ENTs) and emboli to distal territories (EDTs) within the initially compromised arterial field. The 6 distal medium arterial arbors (anterior cerebral artery [ACA], M2–M4 middle cerebral artery [MCA], posterior cerebral artery [PCA], posterior inferior cerebellar artery [PICA], anterior inferior cerebellar artery [AICA], and superior cerebellar artery [SCA]) typically have 25 anatomic segments and give rise to 34 distinct arterial branches nourishing highly differentiated, largely superficial cerebral neuroanatomical regions. DMVOs produce clinical syndromes that are highly heterogenous but frequently disabling. While intravenous fibrinolytics are more effective for distal than proximal occlusions, they fail to recanalize one-half to two-thirds of DMVOs. Early clinical series using recently available, smaller, more navigable stent retriever and thromboaspiration devices suggest EVT for DMVOs is safe, technically efficacious, and potentially clinically beneficial. Collaborative investigations are desirable to enhance imaging recognition of DMVOs; advance device design and technical efficacy; conduct large registry studies using harmonized, common data elements; and complete formal randomized trials, improving treatment of this frequent mechanism of stroke.

IMPORTANCE Clinical evidence of the potential treatment benefit of mechanical thrombectomy for posterior circulation distal, medium vessel occlusion (DMVO) is sparse.OBJECTIVE To investigate the frequency as well as the clinical and safety outcomes of mechanical thrombectomy for isolated posterior circulation DMVO stroke and to compare them with the outcomes of standard medical treatment with or without intravenous thrombolysis (IVT) in daily clinical practice. DESIGN, SETTING, AND PARTICIPANTSThis multicenter case-control study analyzed patients who were treated for primary distal occlusion of the posterior cerebral artery (PCA) of the P2 or P3 segment. These patients received mechanical thrombectomy or standard medical treatment (with or without IVT) at 1 of 23 comprehensive stroke centers in Europe, the United States, and Asia between January 1, 2010, and June 30, 2020. All patients who met the inclusion criteria were matched using 1:1 propensity score matching. INTERVENTIONS Mechanical thrombectomy or standard medical treatment with or without IVT.MAIN OUTCOMES AND MEASURES Clinical end point was the improvement of National Institutes of Health Stroke Scale (NIHSS) scores at discharge from baseline. Safety end point was the occurrence of symptomatic intracranial hemorrhage and hemorrhagic complications were classified based on the Second European-Australasian Acute Stroke Study (ECASSII). Functional outcome was evaluated with the modified Rankin Scale (mRS) score at 90-day follow-up. RESULTSOf 243 patients from all participating centers who met the inclusion criteria, 184 patients were matched. Among these patients, the median (interquartile range [IQR]) age was 74 (62-81) years and 95 (51.6%) were female individuals. Posterior circulation DMVOs were located in the P2 segment of the PCA in 149 patients (81.0%) and in the P3 segment in 35 patients (19.0%). At discharge, the mean NIHSS score decrease was −2.4 points (95% CI, −3.2 to −1.6) in the standard medical treatment cohort and −3.9 points (95% CI, −5.4 to −2.5) in the mechanical thrombectomy cohort, with a mean difference of −1.5 points (95% CI, 3.2 to −0.8; P = .06). Significant treatment effects of mechanical thrombectomy were observed in the subgroup of patients who had higher NIHSS scores on admission of 10 points or higher (mean difference, −5.6; 95% CI, −10.9 to −0.2; P = .04) and in the subgroup of patients without IVT (mean difference, −3.0; 95% CI, −5.0 to −0.9; P = .005). Symptomatic intracranial hemorrhage occurred in 4 of 92 patients (4.3%) in each treatment cohort.CONCLUSIONS AND RELEVANCE This study suggested that, although rarely performed at comprehensive stroke centers, mechanical thrombectomy for posterior circulation DMVO is a safe, and technically feasible treatment option for occlusions of the P2 or P3 segment of the PCA compared with standard medical treatment with or without IVT.

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BackgroundBenefit of thrombectomy in patients with a low initial Alberta Stroke Program Early CT Score (ASPECTS) is still uncertain. We hypothesized that, despite low ASPECTS, patients may benefit from endovascular recanalization if good collaterals are present.MethodsIschemic stroke patients with large vessel occlusion in the anterior circulation and an ASPECTS of ≤5 were analyzed. Collateral status (CS) was assessed using a 5-point-scoring system in CT angiography with poor CS defined as CS=0–1. Clinical outcome was determined using the modified Rankin Scale (mRS) score after 90 days. Edema formation was measured in admission and follow-up CT by net water uptake.Results27/100 (27%) patients exhibited a CS of 2–4. 50 patients underwent successful vessel recanalization and 50 patients had a persistent vessel occlusion. In multivariable logistic regression analysis, collateral status (OR 3.0; p=0.003) and vessel recanalization (OR 12.2; p=0.009) significantly increased the likelihood of a good outcome (mRS 0–3). A 1-point increase in CS was associated with 1.9% (95% CI 0.2% to 3.7%) lowered lesion water uptake in follow-up CT .ConclusionEndovascular recanalization in patients with ASPECTS of ≤5 but good collaterals was linked to improved clinical outcome and attenuated edema formation. Collateral status may serve as selection criterion for thrombectomy in low ASPECTS patients.

Background and Purpose: This study evaluates the benefit of endovascular treatment (EVT) for patients with extensive baseline stroke compared with best medical treatment. Methods: This retrospective, multicenter study compares EVT and best medical treatment for computed tomography (CT)–based selection of patients with extensive baseline infarcts (Alberta Stroke Program Early CT Score ≤5) attributed to anterior circulation stroke. Patients were selected from the German Stroke Registry and 3 tertiary stroke centers. Primary functional end points were rates of good (modified Rankin Scale score of ≤3) and very poor outcome (modified Rankin Scale score of ≥5) at 90 days. Secondary safety end point was the occurrence of symptomatic intracerebral hemorrhage. Angiographic outcome was evaluated with the modified Thrombolysis in Cerebral Infarction Scale. Results: After 1:1 pair matching, a total of 248 patients were compared by treatment arm. Good functional outcome was observed in 27.4% in the EVT group, and in 25% in the best medical treatment group ( P =0.665). Advanced age (adjusted odds ratio, 1.08 [95% CI, 1.05–1.10], P <0.001) and symptomatic intracerebral hemorrhage (adjusted odds ratio, 6.35 [95% CI, 2.08–19.35], P <0.001) were independently associated with very poor outcome. Mortality (43.5% versus 28.9%, P =0.025) and symptomatic intracerebral hemorrhage (16.1% versus 5.6%, P =0.008) were significantly higher in the EVT group. The lowest rates of good functional outcome (≈15%) were observed in groups of failed and partial recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 0/1–2a), whereas patients with complete recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 3) with recanalization attempts ≤2 benefitted the most (modified Rankin Scale score of ≤3:42.3%, P =0.074) compared with best medical treatment. Conclusions: In daily clinical practice, EVT for CT–based selected patients with low Alberta Stroke Program Early CT Score anterior circulation stroke may not be beneficial and is associated with increased risk for hemorrhage and mortality, especially in the elderly. However, first- or second-pass complete recanalization seems to reveal a clinical benefit of EVT highlighting the vulnerability of the low Alberta Stroke Program Early CT Score subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03356392.

Purpose The aim of this study was to analyze sex differences in outcome after thrombectomy for acute ischemic stroke in clinical practice in a large prospective multicenter registry. Methods Data of consecutive stroke patients treated with thrombectomy (June 2015–April 2018) derived from an industry-independent registry (German Stroke Registry–Endovascular Treatment) were prospectively analyzed. Multivariable binary logistic regression analyses were applied to determine whether sex is a predictor of functional independence outcome (defined as a modified Rankin scale [mRS] 0–2) 90 days after stroke. Results In total, 2316 patients were included in the analysis, 1170 (50.5%) were female and 1146 (49.5%) were male. Women were older (median age 78 vs. 72 years; p < 0.001) and more frequently had a prestroke functional impairment defined by mRS >1 (24.8% vs. 14.1%; p < 0.001). In unadjusted analyses, independent outcome at 90 days was less frequent in women (33.2%) than men (40.6%; p < 0.001). Likewise, mortality was higher in women than in men (30.7% vs. 26.4%; p = 0.024). In adjusted regression analyses, however, sex was not associated with outcome. Lower age, a lower baseline National Institutes of Health Stroke Scale score, a higher Alberta Stroke Program Early CT score, prestroke functional independence, successful reperfusion, and concomitant intravenous thrombolysis therapy predicted independent outcome. Conclusion Women showed a worse functional outcome after thrombectomy for acute ischemic stroke in clinical practice; however, after adjustment for crucial confounders sex was not a predictor of outcome. The difference in outcome thus appears to result from differences in confounding factors such as age and prestroke functional status.

Background and Purpose— Poor collateral flow is associated with poor clinical outcome in acute ischemic stroke and may indicate futile recanalization after successful thrombectomy. Pronounced early formation of cerebral ischemic edema may be the link between poor collateral status and declined functional outcome, but this relationship has not been investigated yet. We hypothesized that collateral status is associated with early lesion water uptake as quantitative marker for edema progression. Methods— One hundred seventy-six patients with middle cerebral artery stroke who underwent mechanical thrombectomy were analyzed. Status of cerebral collateral circulation (collaterals status [CS]) was derived using an established 5-point scoring system in admission computed tomography angiography, and good collaterals were defined as CS 3 to 4. Ischemic brain edema dynamics were quantified using early edema progression rate (EPR). EPR was derived from quantitative lesion water uptake in admission computed tomography divided by time from symptom onset to imaging. Good clinical outcome was defined as modified Rankin Scale score 0 to 2 after 90 days. Results— The median EPR was 1.4% per hour (interquartile range, 0.5–3.5%) in patients with good collaterals, which was lower than the median EPR in patients with poor collaterals of 5.8% per hour (interquartile range, 2.1–5.9%; P <0.0001). In multivariable regression analysis, lower CS was significantly and independently associated with higher EPR (1.6% EPR per 1-point CS; P =0.002). A higher EPR was associated with reduced likelihood of good clinical outcome: odds ratio 0.87; (95% CI, 0.76–0.99; P =0.03). Conclusions— Patients with poor CS had significantly higher EPR, which was associated with worse clinical outcome. These patients might benefit from adjuvant antiedematous treatment.