T he majority of the patients having an emergent large vessel occlusion (ELVO) may develop severe and permanent neurological morbidity or death without urgent and successful treatment. Recently published randomized clinical trials have all shown that intra-arterial (IA) treatments in combination with intravenous recombinant tissuetype plasminogen activator (r-tPA) when indicated leads to improved clinical outcomes as compared with standard medical therapy alone. [1][2][3][4] Compared with prior randomized trials that showed no benefit for IA treatment, 5-7 most patients enrolled in these studies received stent-retriever mechanical thrombectomy (MT) that resulted in higher rates of modified thrombolysis in cerebral infarction score (mTICI) 2b or 3 recanalization. Despite high rates of successful recanalization, nearly half of the patients remained functionally dependent (mRS≥3) after 90 days.Background and Purpose-The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shearactivated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. Methods-A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Results-Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1. 28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). Conclusions-A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy. 14 This observation is supported by results of histopathologic exams from animal studies, where extensive endothelial damage was observed after stent retriever usage. [15][16][17] Focal denudation of the vascular endothelium results in exposure of a hi...

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The authors examined the relation between sun exposure and melanoma risk and tested the previously published site-specific association of bikini use and melanoma of the trunk in a study of 130 cases incident between 1976 and 1984 and 300 controls nested within the Nurses' Health Study. A summary variable derived from four measures of sun sensitivity was more closely associated with melanoma than any component measure. There was no association of bikini use at ages 15-20 years with trunk melanoma risk (relative risk (RR) = 0.8, p = 0.7), and the 95% confidence interval (CI) (0.3-2.6) excludes the previously published estimate. High frequency of swimsuit use outdoors at ages 15-20 years was associated with increased melanoma risk among sun-sensitive women (RR = 6.4, 95% CI 1.7-23.8, p = 0.006), but appeared to be protective among sun-resistant women (RR = 0.3, 95% CI 0.1-1.0, p = 0.06). These findings suggest that the risk of trunk melanoma associated with bikini use is at most modest and that sun-sensitive women may increase their risk of melanoma with frequent sun exposures, but that sun-resistant women do not, presumably because they develop a photoprotective tan.

We examined the relationship between self-reported mole counts and cutaneous melanoma with respect to anatomic site in 110 case and 231 control female nurses. Counts of moles on the lower leg were better predictors of melanoma risk than were counts of moles on the arm. The relative risk for the highest quintile of lower leg mole counts versus no lower leg moles was 4.2. Mole counts at each site (arm, thigh, and lower leg) were associated with risk of melanoma of the trunk and lower leg, but none were associated with the risk of melanoma of the upper extremity. The absence of direct site-specificity suggests that mole counts primarily indicate systemic melanoma risk, rather than direct risk from the moles themselves.

The relation of the presence of moles (nevi) on all four limbs to risk of cutaneous malignant melanoma was explored among 98 incident cases aged 32-59 years at diagnosis and 190 age-matched controls drawn from the Nurses' Health Study, a prospective cohort of female nurses in the United States. Cases diagnosed during follow-up from 1976 to 1982 were included in this study. Participants reported counts of all moles and raised moles alone on postal questionnaires. Distributions of moles were similar for right and left sides on upper and lower limbs for cases and controls. Counts declined with increasing age for all women, from a median of 15 for the youngest tertile of controls (aged 36-46 years) to three for the oldest (aged 54-62 years). Cases had more moles than did controls (medians of 23 and 9, respectively, for total moles on all four limbs): The presence of any mole on a limb gave relative risks for melanoma ranging from 2.2 (95% confidence interval (CI) = 1.2-4.0) for one or more moles on an arm to 2.9 (95% CI = 1.6-5.3) for one or more moles on the lower limb. For raised moles, relative risks were 1.7 (95% CI = 1.0-2.7) for arm, 2.1 (95% CI = 1.3-3.5) for lower limb, and 3.5 (95% CI = 2.0-6.3) for leg (below knee). The highest site-specific risk (i.e., for any moles on the same limb as the melanoma vs. no moles on that limb) was for moles on the lower limb (relative risk = 5.0 (95% CI = 1.8-13.5)). There were positive and significant trends in overall and site-specific risk with increasing numbers of moles on all limbs when absolute mole counts were considered, e.g., for total moles on all four limbs combined, chi for trend = 4.0, one-sided p less than 0.001, with relative risk for more than 100 moles versus none of 6.0. Inclusion of sun exposure and other constitutional factors in logistic regression analyses did not alter these observed relations between the presence of moles and risk of melanoma.