Mismatch-based delayed thrombolysis: a meta-analysis

<p><b>Background and Purpose</b>: Clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. The use of "mismatch" imaging to identify patients for delayed treatment has face validity and has been used in case series and clinical trials. We undertook a meta-analysis of relevant trials to examine whether present evidence supports delayed thrombolysis among patients selected according to mismatch criteria.</p> <p><b>Methods</b>: We collated outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pretreatment imaging. We selected the trials on the basis of a systematic search of the Web of Knowledge. We compared favorable outcome, reperfusion and/or recanalization, mortality, and symptomatic intracerebral hemorrhage between the thrombolyzed and nonthrombolyzed groups of patients and the probability of a favorable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from poststroke onset. Results are expressed as adjusted odds ratios (a-ORs) with 95% CIs. Heterogeneity was explored by test statistics for clinical heterogeneity, I2 (inconsistency), and L’Abbé plot.</p> <p><b>Results</b>: We identified articles describing the DIAS, DIAS II, DEDAS, DEFUSE, and EPITHET trials, giving a total of 502 mismatch patients thrombolyzed beyond 3 hours. The combined a-ORs for favorable outcomes were greater for patients who had successful reperfusion (a-OR=5.2; 95% CI, 3 to 9; I2=0%). Favorable clinical outcome was not significantly improved by thrombolysis (a-OR=1.3; 95% CI, 0.8 to 2.0; I2=20.9%). Odds for reperfusion/recanalization were increased among patients who received thrombolytic therapy (a-OR=3.0; 95% CI, 1.6 to 5.8; I2=25.7%). The combined data showed a significant increase in mortality after thrombolysis (a-OR=2.4; 95% CI, 1.2 to 4.9; I2=0%), but this was not confirmed when we excluded data from desmoteplase doses that were abandoned in clinical development (a-OR=1.6; 95% CI, 0.7 to 3.7; I2=0%). Symptomatic intracerebral hemorrhage was significantly increased after thrombolysis (a-OR=6.5; 95% CI, 1.2 to 35.4; I2=0%) but not significant after exclusion of abandoned doses of desmoteplase (a-OR=5.4; 95% CI, 0.9 to 31.8; I2=0%).</p> <p><b>Conclusions</b>: Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization. Recanalization/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral hemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.</p&gt

Year-round growth potential and moisture stress tolerance of buckwheat (Fagopyrum esculentum L.) under fragile hill ecosystems of the Eastern Himalayas (India)

IntroductionUnder a changing climate, the fragile ecosystems of the Eastern Himalayas (EH) are persistently challenged by prolonged dry spells and erratic rainfall. Identification of suitable high-yielding crops with higher moisture stress tolerance and adaptability is paramount for the region. Although the region received a good amount of rainfall in the rainy season, the winter months, viz., November to March, rarely received any rain. Even within the rainy season, there are several intermittent drought spells that hinder crop productivity.MethodsThe present study has used field and microcosm experiments to assess the year-round cultivation potential and extent of moisture stress tolerance in the lesser-known buckwheat crop of the region.Results and discussionSowing of buckwheat from mid-September to mid-December produced better grain yield, the highest being when sowing in October (9.83 q ha−1) and the crop was found suitable to grow all through the year for higher green biomass (12.6–38.4 q ha−1). The moisture stress tolerance of buckwheat was significantly enhanced by increased total root length and root surface area by 12.4 and 34.7%, respectively. Increased photo-protective carotenoids, chlorophyll b, and favorable stomatal attributes with substantial epicuticular wax have significantly improved the moisture stress tolerance of Buckwheat. In addition, leaf proline was found 25.4% higher and total soluble protein, reducing sugar, and cell membrane stability were found 29.2, 38.1, and 36.5% lower compared to the control, respectively. A significantly lower rate of water loss (25.6%) with its stomatal and non-stomatal adaptations and versatile pollen structural traits under moisture stress over control, make the buckwheat crop potentially more stress tolerant and economical crop for EH of India

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Microstructure and Mechanical Behavior of Friction Stir Processed Ultrafine Grained Al-Mg-Sc Alloy

Twin-roll cast (TRC) Al-Mg-Sc alloy was frictionstir processed (FSP) to obtain ultrafine grained (UFG) microstructure. Average grain size of TRC alloy in as-received (AR) condition was 19.0 ± 27.2 μm. The grain size reduced to 0.73 ± 0.44 μm after FSP. About 80% of the grains were smaller than 1 μm in FSP condition. FSP resulted into 80% of the grain boundaries to have high angle grain boundary (HAGBs) character. Uniaxial tensile testing of UFG alloy showed an increase in yield strength (YS) and ultimate tensile strength (UTS) (by ∼100 MPa each) of the alloy with a very marginal decrease in total and uniform elongation (total - 27% in AR and 24% in UFG and uniform - 19% in AR and 14% in UFG). A theoretical model predicted that the grain refinement cannot take place via discontinuous dynamic recrystallization. Zener pinning model correctly predicted the grain size distribution for UFG alloy. From work hardening behaviors in both the conditions, it was concluded that grain boundary spacing is more important than the character of grain boundaries for influencing extent of uniform deformation of an allo

Critical Grain Size for Change in Deformation Behavior in Ultrafine Grained Al-Mg-Sc Alloy

Experimental evaluation of critical grain size for the change in deformation behavior from strain hardening to strain softening in ultrafine grained (UFG) Al-Mg-Sc was carried out. UFG alloy was processed using friction stir processing (FSP). Two different average grain sizes were obtained by changing the FSP parameters. UFG alloy with grain size larger than the subgrain size showed sufficient strain hardening during tensile testing, whereas smaller grain size material exhibited strain softening

The Effect of Friction Stir Processing on the Microstructure and Mechanical Properties of Equal Channel Angular Pressed 5052Al Alloy Sheet

In this study, equal channel angular pressed (ECAP) 5052Al alloy sheet was friction stir processed (FSP). This was carried out to understand the effect of FSP on the microstructure and mechanical properties of the ECAP sheet. FSP led to further grain refinement and a tighter distribution of grains. Fraction of high-angle grain boundaries changed from 15% in ECAP condition to more than 70% after FSP. Although FSP caused lowering of yield strength (YS) and ultimate tensile strength (UTS), it resulted into a substantial improvement in uniform deformation region of the tensile sample (from 1.3% in as-received condition to 12.9% in FSP condition). Strain hardening rate (SHR) analysis showed lowering of recovery rate on FSP. A static grain growth model correctly predicted the average grain size obtained after FSP. Existing grain boundary, solid solution, and dislocation strengthening models were used to estimate the YS of 5052Al alloy in both the conditions. The strengthening model was able to predict the YS of the alloy in as-received and FSP conditions very well

Assessment of design runoff curve number for Maithon watershed

50-55Estimation of storm event runoff is one of the major activities in applied hydrology for ungauged small watersheds. There exist a myriad computer models in the field of water resources and irrigation engineering and the most comprehensive and popular ones use the Soil Conservation Service (SCS) curve number methodology to determine the rainfall-excess from rainfall event. The SCS Curve Number (CN) (SCS-CN) technique is one of the most popular and well accepted techniques for it is a simple approach for direct runoff estimation. Its parameter CN is a measure of water retention by a given combination of soil and vegetation and varies from 0 (no runoff) to 100 (all rainfall becomes runoff). In this study, considering each day’s rainfall and corresponding runoff as an event, the SCS-CN method is employed to longterm daily rainfall-runoff data of Maithon watershed located in Jharkhand (India). A simple approach has been suggested for derivation of the design runoff CN for different durations, antecedent moisture conditions (AMCs), and return periods for use in the SCS-CN methodology. The derived design CN values are tested for their validity using the design runoff computed from observed data conventionally. The match between the CN-generated design runoff and the conventional one is found to be satisfactory for return periods up to 10-year return period for the studied watershed

Can bone-specific alkaline phosphatase be a marker of vascular calcification in type 2 diabetes mellitus?

Background and Aims: Alkaline phosphatase (ALP) enzyme has been linked to vascular calcification. Unexplained elevations in serum ALP levels have been reported in patients with type 2 diabetes mellitus (T2DM). We assessed bone-specific alkaline phosphatase (BAP) levels in patients with T2DM who had unexplained ALP elevations and studied the association between BAP and other markers of vascular calcification. Methods: Patients with T2DM who had high serum ALP in the absence of known causes of ALP elevation were studied. The control group was T2DM patients with normal ALP. We measured the serum levels of BAP along with the leptin, fetuin-A, and vitamin K2 levels. Ankle–brachial index (ABI) was also measured in both groups. Results: Serum BAP levels were significantly higher in the group with high ALP when compared with the normal ALP group. A significant positive correlation was present between BAP and serum fetuin-A as well as between BAP and Vit K2 levels. There was no correlation between BAP and serum leptin. ABI was comparable between the two groups. Conclusions: Patients with T2DM may have unexplained elevation in ALP due to an increase in BAP. Elevation in BAP may be associated with other markers of vascular calcification suggesting an increased risk of vascular calcification