Impact of alkaline phosphatase on clinical outcomes in patients with ischemic stroke: a nationwide registry analysis

BackgroundData on the association between serum alkaline phosphatase (ALP) levels and clinical outcomes in patients with ischemic stroke (IS) are inconsistent and limited. Therefore, this study aimed to investigate the correlation between ALP and prognosis in patients with IS.MethodsPatients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from the Third China National Stroke Registry were divided into four groups according to the quartiles of serum ALP levels on admission. Cox proportional hazards and logistic regression models were used to evaluate the correlation between ALP and the risk of all-cause mortality, disability (modified Rankin Scale (mRS) score 3–5), and poor functional outcomes (mRS score 3–6).ResultsA total of 11,405 patients were included in the study. Higher levels of ALP were associated with all-cause mortality at 3 months (adjusted hazard ratio [HR] per standard deviation [SD]: 1.16; 95% confidence interval (CI): 1.07–1.27; p = 0.001) and 1 year (adjusted HR: 1.11; 95% CI: 1.03–1.20; p = 0.010). At the 3-month follow-up, each SD increase of ALP was associated with a 12 and 14% higher risk of disability (adjusted odds ratio (OR): 1.12; 95% CI: 1.06–1.18; p < 0.001) and poor functional outcomes (adjusted OR: 1.14; 95% CI: 1.08–1.20; p < 0.001). Similar results were observed at the 1-year follow-up. Higher ALP levels were associated with an increased risk of all-cause mortality, disability, and poor functional outcomes in patients with “others” subtypes (including other determined etiology and undetermined etiology) (p < 0.05).ConclusionElevated ALP levels were associated with an increased risk of all-cause mortality, disability, and poor function outcomes in patients with IS. Heterogeneity was observed among the subtypes of different etiologies

Association of CYP2C19 Loss-of-Function Metabolizer Status With Stroke Risk Among Chinese Patients Treated With Ticagrelor-Aspirin vs Clopidogrel-Aspirin: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: The Clopidogrel With Aspirin in High-Risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that ticagrelor-aspirin combination therapy reduced the risk of stroke compared with a clopidogrel-aspirin combination among carriers of CYP2C19 loss-of-function (LOF) alleles after a transient ischemic attack (TIA) or minor ischemic stroke. However, the association between the degree of CYP2C19 LOF and ideal treatment allocation remains unknown.Objective: To investigate whether the efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin are consistent with the expected degree of CYP2C19 LOF after TIA or minor stroke.Design, Setting, and Participants: CHANCE-2 was a multicenter, double-blind, double-dummy, placebo-controlled randomized clinical trial. Patients were enrolled at 202 centers in China from September 23, 2019, through March 22, 2021. Patients with at least two *2 or *3 alleles (*2/*2, *2/*3, or *3/*3) according to point-of-care genotyping were classified as “poor metabolizers,” and those with one *2 or *3 allele (*1/*2 or *1/*3) were classified as “intermediate metabolizers.”Interventions: Patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or clopidogrel (300-mg loading dose on day 1 followed by 75 mg/d for days 2-90). All patients received aspirin (75- to 300-mg loading dose followed by 75 mg/d for 21 days).Main Outcomes and Measures: The primary efficacy outcome was a new ischemic or hemorrhagic stroke. The secondary efficacy outcome was a composite of new clinical vascular events and individual ischemic stroke events within 3 months. The primary safety outcome was severe or moderate bleeding. Analyses were performed according to the intention-to-treat principle.Results: Of the 6412 patients enrolled, the median age was 64.8 years (IQR, 57.0-71.4 years), and 4242 patients (66.2%) were men. Of the 6412 patients, 5001 (78.0%) were intermediate metabolizers, and 1411 (22.0%) were poor metabolizers. The primary outcome occurred less often with ticagrelor-aspirin vs clopidogrel-aspirin, irrespective of metabolizer status (6.0% [150 of 2486] vs 7.6% [191 of 2515]; hazard ratio [HR], 0.78 [95% CI, 0.63-0.97] among intermediate metabolizers and 5.7% [41 of 719] vs 7.5% [52 of 692]; HR, 0.77 [95% CI, 0.50-1.18] among poor metabolizers; P = .88 for interaction). Patients taking ticagrelor-aspirin had a higher risk of any bleeding event compared with those taking clopidogrel-aspirin, irrespective of metabolizer status: 5.4% (134 of 2486) vs 2.6% (66 of 2512) (HR, 2.14 [95% CI, 1.59-2.89]) among intermediate metabolizers and 5.0% (36 of 719) vs 2.0% (14 of 692) (HR, 2.99 [95% CI, 1.51-5.93]) among poor metabolizers (P = .66 for interaction).Conclusions and Relevance: This prespecified analysis of a randomized clinical trial found no difference in treatment effect between poor and intermediate CYP2C19 metabolizers. The relative clinical efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin were consistent across CYP2C19 genotypes.Trial Registration: ClinicalTrials.gov Identifier: NCT0407873

Limb development genes underlie variation in human fingerprint patterns

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery

Ticagrelor vs Clopidogrel in CYP2C19 loss-of-function carriers with Stroke or TIA

BACKGROUNDComparisons between ticagrelor- aspirin and clopidogrel-aspirin in CYP2C19 loss-of-function carriers have not been well studied for secondary stroke prevention.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of 6,412 patients with a minor ischemic stroke or TIA who carried CYP2C19 LOF alleles determined by point-of-care testing. Patients were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio to receive ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or clopidogrel (300 mg loading dose on day 1 followed by 75 mg per day for days 2 through 90), plus aspirin (75-300 mg loading dose followed by 75 mg daily for 21 days). The primary efficacy outcome was stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTSStroke occurred within 90 days in 191 (6.0%) versus 243 (7.6%), respectively (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P=0.008). Moderate or severe bleeding occurred in 9 patients (0.3%) in the ticagrelor-aspirin group and in 11 patients (0.3%) in the clopidogrel-aspirin group; any bleeding event occurred in 170 patients (5.3%) vs 80 (2.5%), respectively. CONCLUSIONSAmong Chinese patients with minor ischemic stroke or TIA within 24 hours after symptoms onset who were carriers of CYP2C19 loss-of-function alleles, ticagrelor- aspirin was modestly better than clopidogrel-aspirin for reducing the risk of stroke but was associated with more total bleeding events at 90 days. (CHANCE-2 ClinicalTrials.gov number, NCT04078737.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

BackgroundDual antiplatelet treatment has been shown to reduce recurrence of stroke compared to aspirin alone when initiated early after an acute stroke. The effect of clopidogrel and aspirin versus aspirin alone within 72 hours of acute cerebral ischemia from atherosclerosis has not been well studied.MethodsWe conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial in patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause, not receiving thrombolysis or thrombectomy in 222 hospitals in China. Patients were randomly assigned within 72 hours after symptom onset in a 1:1 ratio, to receive clopidogrel (300mg on day 1, 75mg daily on days 2-90) and aspirin (100-300mg on day1, 100mg daily on days 2-21), or clopidogrel placebo and aspirin (100-300mg on day1, 100mg daily on days 2-90). There was no interaction between this component of the factorial trial design trial and a second part that tested immediate vs delayed stain treatment and is reported separately. The primary efficacy outcome was a new stroke, and the primary safety outcome was moderate-to-severe bleeding, both within 90 days.ResultsA total of 6100 patients were enrolled, 3050 assigned to each trial group. The qualifying event for enrollment was TIA in 13%. Approximately 13% of patients were assigned to a treatment group within 24 hours and 87% were assigned between 24 and 72 hours of onset of stroke. A new stroke occurred in 222 (7.3%) in the clopidogrel-aspirin group, and 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.008). Moderate-to-severe bleeding occurred in 27 (0.9%) and 13 patients (0.4%), respectively (hazard ratio, 2.08; 95% CI, 1.07-4.04, P=0.03).ConclusionsAmong patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin initiated within 72 hours of onset was superior to aspirin alone in reducing the risk of new stroke at 90 days but was associated with a low but increased risk of moderate-to-severe bleeding

Gap-Filling of 8-Day Terra MODIS Daytime Land Surface Temperature in High-Latitude Cold Region with Generalized Additive Models (GAM)

Land surface temperature (LST) is a crucial parameter driving the dynamics of the thermal state on land surface. In high-latitude cold region, a long-term, stable LST product is of great importance in examining the distribution and degradation of permafrost under pressure of global warming. In this study, a generalized additive model (GAM) approach was developed to fill the missing pixels of the MODIS/Terra 8-day Land Surface Temperature (MODIS LST) daytime products with the ERA5 Land Skin Temperature (ERA5ST) dataset in a high-latitude watershed in Eurasia. Comparison at valid pixels revealed that the MODIS LST was 4.8–13.0 °C higher than ERA5ST, which varies with land covers and seasons. The GAM models fairly explained the LST differences between the two products from multiple covariates including satellite-extracted environmental variables (i.e., normalized difference water index (NDWI), normalized difference vegetation index (NDVI), and normalized difference snow index (NDSI) as well as locational information. Considering the dramatic seasonal variation of vegetation and frequent snow in the cold region, the gap-filling was conducted in two seasons. The results revealed the root mean square errors (RMSE) of 2.7 °C and 3.4 °C between the valid MODIS LST and GAM-simulated LST data in the growing season and snowing season, respectively. By including the satellite-extracted land surface information in the GAM model, localized variations of land surface temperature that are often lost in the reanalysis data were effectively compensated. Specifically, land surface wetness (NDWI) was found to be the greatest contributor to explaining the differences between the two products. Vegetation (NDVI) was useful in the growing season and snow cover (NDSI) cannot be ignored in the snow season of the study region. The km-scale gap-filled MODIS LST products provide spatially and temporally continuous details that are useful for monitoring permafrost degradation in cold regions in scenarios of global climate change

Effect of Hyporheic Exchange on Macroinvertebrate Community in the Weihe River Basin, China

The effect of hyporheic exchange on macroinvertebrates is a significant topic in ecohydraulics. A field study was conducted during May and June 2017 to investigate the impacts of magnitude and patterns of hyporheic exchange on the sediment macroinvertebrate community in the Weihe River basin. The results demonstrate that upwelling flows cause resuspension of riverbed sediment, increasing the proportion of swimmer groups (such as Baetidae) in the macroinvertebrate community. However, large resuspension of river bed sediment results in a reduced abundance of macroinvertebrates. By controlling the transport processes of dissolved oxygen (DO), dissolved organic carbon (DOC), nutrients, temperature, and different patterns of hyporheic exchange strongly influence the structure of macroinvertebrate communities. Downwelling is more likely to produce rich invertebrate communities than upwelling. The magnitude for the hyporheic flux of 150–200 mm/d was optimal for the macroinvertebrate community in the Weihe River Basin. Above or below this rate results in a decline in community abundance and diversity. We suggest that research is conducted to better understand the effects of hyporheic exchange across bedforms on macroinvertebrate communities. The study supports any activities to preserve the ecological functions and health of rivers dominated by fine-grained sediments

The Electric–Thermal Effect of a Carbon-Fibre-Reinforced Epoxy Composite and Its Corresponding Mechanical Properties

In this work, the electric–thermal effect of a carbon-fibre-reinforced epoxy composite (CFRE) panel was studied, as well as the influence of the electric heating treatment on the mechanical properties of the composite. It was observed that the temperature of the composite increased rapidly once the current was loaded, and the equilibrium surface temperature was reached within 2 min. The electric–thermal effect and mechanical properties depended on both the current loading time and the current intensity. At 5A, the flexural modulus and strength of the CFRE increased before decreasing with the current loading time. Under the same treatment time, the flexural strength of the samples treated with 5A was evidently larger than that under the small current, and all the treated samples displayed enhanced flexural strength compared to that of untreated samples. The results depicted that the low-current treatment and short time could improve the interfacial properties between CF/epoxy, along with enhancing the flexural properties of the samples. However, a large amount of the joule heating from the larger current and a more extensive time frame is predicted to cause irreversible defects to the composite, which consequently leads to the reduction in flexural strength of the composite. TGA results indicated decreased thermal stability of the CFRE composite panels after the electric heating treatment was applied