Reteplase versus Alteplase for Acute Ischemic Stroke.

BACKGROUND: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. METHODS: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. RESULTS: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). CONCLUSIONS: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).

Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment within 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered within 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).

Safety and Efficacy of Reteplase Versus Alteplase for Acute Ischemic Stroke: A Phase 2 Randomized Controlled Trial.

BACKGROUND: Reteplase is a more affordable new-generation thrombolytic with a prolonged half-life. We aimed to determine the safety dose range of reteplase for patients with acute ischemic stroke within 4.5 hours of onset. METHODS: This is a multicenter, prospective, randomized controlled, open-label, blinded-end point phase 2 clinical trial. Patients with acute ischemic stroke aged between 18 and 80 years who were eligible for standard intravenous thrombolysis were enrolled from 17 centers in China and randomly assigned (1:1:1) to receive intravenous reteplase 12+12 mg, intravenous reteplase 18+18 mg, or intravenous alteplase 0.9 mg/kg. The primary safety outcome was symptomatic intracranial hemorrhage (SITS definition) within 36 hours. The primary efficacy outcome was the proportion of patients with the National Institutes of Health Stroke Scale score of no more than 1 or a decrease of at least 4 points from the baseline at 14 days after thrombolysis. RESULTS: Between August 2019 and May 2021, 180 patients were randomly assigned to reteplase 12+12 mg (n=61), reteplase 18+18 mg (n=67), or alteplase (n=52). Four patients did not receive the study agent. Symptomatic intracranial hemorrhage occurred in 3 of 60 (5.0%) in the reteplase 12+12 mg group, 1 of 66 (1.5%) in the reteplase 18+18 mg group, and 1 of 50 (2.0%) in the alteplase group (P=0.53). The primary efficacy outcome in the modified intention-to-treat population occurred in 45 of 60 (75.0%) in the reteplase 12+12 mg group (odds ratio, 0.85 [95% CI, 0.35-2.06]), 48 of 66 (72.7%) in the reteplase 18+18 mg group (odds ratio, 0.75 [95% CI, 0.32-1.78]), and 39 of 50 (78.0%) in alteplase group. CONCLUSIONS: Reteplase was well tolerated in patients with acute ischemic stroke within 4.5 hours of onset in China with a similar efficacy profile to alteplase. The efficacy and appropriate dosage of reteplase for patients with acute ischemic stroke need prospective validation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04028518.

Associations of life's essential 8 with extent of multi-territorial atherosclerotic plaques and stenosis: a cross-sectional study.

BACKGROUND: Life's Essential 8 (LE8), the recently updated construct for quantifying cardiovascular health, is related to the risks of cardiovascular events. The present study aimed to evaluate associations of LE8 score with the multi-territorial extent of atherosclerosis in a community-dwelling population. METHODS: Data were derived from the baseline cross-sectional survey of the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in Lishui City. The LE8 included overall, medical and behavior LE8 scores, and were categorized as low (< 60), moderate (60-<80), and high (≥ 80) groups. Vascular magnetic resonance imaging was used to evaluate intracranial and extracranial arteries; thoracoabdominal computed tomography angiography to evaluate coronary, subclavian, aorta, renal, ilio-femoral arteries; and ankle-brachial index to evaluate peripheral arteries. The presence of atherosclerotic plaque or stenosis in any territory was defined as plaque or vascular stenosis with 1 territory affected or more in these arteries. The extent of atherosclerotic plaques or stenosis was assessed according to the number of these 8 vascular sites affected, and graded as four grades (none, single territory, 2-3 territories, 4-8 territories). RESULTS: Of 3065 included participants, the average age was 61.2 ± 6.7 years, and 53.5% were women (n = 1639). The moderate and high overall LE8 groups were associated with lower extent of multi-territorial plaques [common odds ratio (cOR) 0.44, 95% confidence interval (CI), 0.35-0.55; cOR 0.16, 95%CI, 0.12-0.21; respectively] and stenosis (cOR 0.51, 95%CI, 0.42-0.62; cOR 0.16, 95%CI, 0.12-0.21; respectively) after adjustment for potential covariates. Similar results were observed for medical LE8 score with the extent of multi-territorial plaques and stenosis (P < 0.05). We also found the association between behavior LE8 score and the extent of multi-territorial stenosis (P < 0.05). CONCLUSIONS: The higher LE8 scores, indicating healthier lifestyle, were associated with lower presence and extent of atherosclerotic plaque and stenosis in southern Chinese adults. Prospective studies are needed to further validate these findings.

Mediation of Systemic Inflammation on Insulin Resistance and Prognosis of Nondiabetic Patients With Ischemic Stroke.

BACKGROUND: Insulin resistance is associated with stroke recurrence and poor functional outcomes of nondiabetic patients with ischemic stroke. The study aimed to investigate whether the association between insulin resistance and the prognosis of nondiabetic patients with ischemic stroke was mediated by systematic inflammation. METHODS: Patients with ischemic stroke but without a history of diabetes who were enrolled in CNSR-III (Third China National Stroke Registry) were included in the study and followed up for 1 year after stroke onset. Insulin resistance was determined by using the homeostasis model assessment for insulin resistance (HOMA-IR) method. hs-CRP (high-sensitivity C-reactive protein) and Lp-PLA2 (lipoprotein-associated phospholipase A2) activity were measured at baseline. The primary outcome was stroke recurrence, and other outcomes included composite vascular events, mortality, and poor functional outcome (modified Rankin Scale score, 3-6). Multivariable Cox or logistic regression analyses were performed to estimate the association between HOMA-IR and the study outcomes. A mediation analysis was performed to examine the relationship between insulin resistance and the study outcomes mediated by systemic inflammation. RESULTS: Among a total of 3808 nondiabetic patients with ischemic stroke who were included in the study, the median HOMA-IR was 1.79 (interquartile range, 1.05-2.97). After adjustments for potential confounders, higher HOMA-IR quartiles were associated with higher risks of stroke recurrence, ischemic stroke, and composite vascular events, especially in the large artery atherosclerosis subtype. hs-CRP partially mediated the association between the HOMA-IR index and the prognosis of ischemic stroke (mediation proportion, 5.9% for stroke recurrence and 7.5% for composite vascular events). No evidence of Lp-PLA2 activity mediating the association of insulin resistance with stroke outcomes was observed. CONCLUSIONS: Our study found that insulin resistance was associated with poor clinical outcomes in nondiabetic patients with ischemic stroke, which was partially mediated by hs-CRP with a modest amount.

Association of insulin resistance with intra- and extra-cranial atherosclerotic burden in the nondiabetic community population.

AIMS: Few population-based studies have investigated the association between insulin resistance and atherosclerotic burden in intra- and extra-cranial arteries. The purpose of this study is to explore the relationship between insulin resistance and intra- and extra-cranial atherosclerotic burden in community-based nondiabetic participants. METHODS: This is a cross-sectional analysis from a population-based prospective cohort-PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China. The homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI0-120) were stratified by the quartiles, respectively. The atherosclerotic presence of plaques and burden was evaluated by high-resolution MRI. Binary or ordinal logistic regression was performed to assess the association between HOMA-IR or ISI0-120 and the presence and burden of atherosclerosis. RESULTS: Among the 2754 participants, the mean age was 60.9 ± 6.6 years, and 1296 (47.1%) were males. Compared with the lowest quartile of HOMR-IR, the highest quartile of HOMA-IR (indicating a higher level of insulin resistance) was associated with an increased presence of plaques (OR:1.54, 95% CI:1.14-2.08), and atherosclerotic burden (OR:1.53, 95%CI:1.14-2.07) in intracranial arteries. Meanwhile, we observed a similar relationship between HOMA-IR and the presence or burden in extracranial atherosclerosis. The first (indicating a higher level of insulin resistance) quartiles of ISI0-120 were associated with the intracranial plaques (Q1, OR:1.56, 95%CI:1.16-2.11) and atherosclerotic burden (Q1, OR:1.57, 95%CI:1.17-2.12), but not extracranial plaques or atherosclerotic burden, compared with the fourth quartile of ISI0-120. CONCLUSIONS: Insulin resistance was associated with an increased intra-and extra-cranial atherosclerotic burden in the nondiabetic elderly Chinese population.

Experience with 2 years' intervention to progressively reduce salt supply to kitchens in elderly care facilities-challenges and further research: post hoc analysis of the DECIDE-Salt randomized clinical trial.

BACKGROUND: Progressive reduction of sodium intake is an attractive approach for addressing excessive salt intake, but evidence for this strategy in real practice is limited. We aimed to determine the feasibility, effectiveness, and safety of a progressive sodium intake reduction intervention in real-world setting. METHODS: We randomized 48 residential elderly care facilities in China, with 1612 participants aged 55 years and older, to either progressive reduction (PR, 24 facilities) or no reduction (NR, 24 facilities) of the supply of study salt to the kitchens of these facilities for 2 years. The primary efficacy outcome was systolic blood pressure (SBP) at any scheduled follow-up visit. Secondary efficacy outcomes included diastolic blood pressure (DBP) at any scheduled follow-up visit, and major adverse cardiovascular events (comprising non-fatal stroke, non-fatal myocardial infarction, hospitalized non-fatal heart failure, or vascular death) and total mortality. The perception of food saltiness, the addition of out-of-study salt in meals, and 24-h urinary sodium excretion were used as process indicators. RESULTS: Pre-specified analysis per randomization found no effect of the intervention on the 2-year overall mean systolic and diastolic blood pressure (SBP, DBP) and any other outcomes. However, post hoc analysis showed that the intervention effect on blood pressure varied over multiple follow-up visits (p for interaction < 0.046) and presented favorable differences at the 24-month visit (SBP = - 3.0 mmHg, 95%CI = - 5.6, - 0.5; p = 0.020; DBP = - 2.0 mmHg, 95%CI - 3.4, - 0.63; p = 0.004). The effect on 24-h sodium was non-significant (- 8.4 mmol, 95%CI = - 21.8 to 4.9, p = 0.216), though fewer participants with NR than with PR reported food tasting bland (odds ratio 0.46; 95%CI 0.29 to 0.73; p = 0.001). Reporting of bland food taste and other process measures indicated that intervention delivery and adherence were not fully achieved as designed. CONCLUSIONS: The experience of this real-world study demonstrated that achieving acceptability and sustainability of the progressive sodium intake reduction strategy among older adults was challenging, but it has shown potential for effectiveness in these and potentially other residential settings if the lessons of DECIDE-Salt are applied in further studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03290716).

Association of metabolic dysfunction-associated fatty liver disease with systemic atherosclerosis: a community-based cross-sectional study.

BACKGROUND: Data are limited on the association of metabolic dysfunction-associated fatty liver disease (MAFLD) with systemic atherosclerosis. This study aimed to examine the relationship between MAFLD and the extent of atherosclerotic plaques and stenosis, and presence of polyvascular disease (PolyVD). METHODS: In this cross-sectional study, MAFLD was diagnosed based on the presence of metabolic dysfunction (MD) and fatty liver disease (FLD). MAFLD was divided into three subtypes: MAFLD with diabetes mellitus (DM), MAFLD with overweight or obesity (OW), as well as MAFLD with lean/normal weight and at least two metabolic abnormalities. Atherosclerosis was evaluated, with vascular magnetic resonance imaging for intracranial and extracranial arteries, thoracoabdominal computed tomography angiography for coronary, subclavian, aorta, renal, iliofemoral arteries, and ankle-brachial index for peripheral arteries. The extent of plaques and stenosis was defined according to the number of these eight vascular sites affected. PolyVD was defined as the presence of stenosis in at least two vascular sites. RESULTS: This study included 3047 participants, with the mean age of 61.2 ± 6.7 years and 46.6% of male (n = 1420). After adjusting for potential confounders, MAFLD was associated with higher extent of plaques (cOR, 2.14, 95% CI 1.85-2.48) and stenosis (cOR, 1.47, 95% CI 1.26-1.71), and higher odds of presence of PolyVD (OR, 1.55, 95% CI 1.24-1.94) as compared with Non-MAFLD. In addition, DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD (All P < 0.05). However, lean-MAFLD was only associated with the extent of atherosclerotic plaques (cOR, 1.63, 95% CI 1.14-2.34). As one component of MAFLD, FLD per se was associated with the extent of plaques and stenosis in participants with MAFLD. Furthermore, FLD interacted with MD to increase the odds of presence of systemic atherosclerosis (P for interaction ≤ 0.055). CONCLUSIONS: MAFLD and its subtypes of DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD. This study implicated that FLD might be a potential target of intervention for reducing the deleterious effects of MAFLD on systemic atherosclerosis.

Association of intracranial atherosclerosis with cerebral small vessel disease in a community-based population.

BACKGROUND AND PURPOSE: The purpose of this study was to explore the relationship between intracranial atherosclerosis and cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents of Lishui, China in the PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study were involved. Intracranial atherosclerosis was grouped by the severity of intracranial artery plaques with stenosis and burden. Four imaging markers including lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMBs), and perivascular spaces (PVS) as well as the CSVD burden scores were assessed. Logistic regression or ordinal logistic regression models with odds ratio (OR) or common OR (cOR) were used to estimate the relationship between intracranial atherosclerosis and CSVD markers and burdens. RESULTS: The mean age was 61.20 ± 6.68 years, and 1424 (46.52%) were men among 3061 participants included at baseline. Intracranial atherosclerotic burden was associated with the severity of the lacunes (OR = 4.18, 95% confidence interval [CI] = 1.83-9.58), modified WMH burden (cOR = 1.94, 95% CI = 1.01-3.71), presence of CMBs (OR = 2.28, 95% CI = 1.05-4.94), and CMB burden (OR = 2.23, 95% CI = 1.03-4.80). However, it was not associated with the WMH burden and PVS. Intracranial atherosclerotic burden was associated with CSVD burden (Wardlaw: cOR = 2.73, 95% CI = 1.48-5.05; Rothwell: cOR = 2.70, 95% CI = 1.47-4.95). The association between intracranial atherosclerosis and CSVD was obvious in participants with both anterior and posterior circulation artery stenosis. CONCLUSIONS: Based on a Chinese community population, there may be an association between intracranial atherosclerosis and CSVD, but its mechanism in relation to vascular risk factors still needs to be clarified.

Adherence to a healthy lifestyle and brain structural imaging markers.

Previous research has linked specific modifiable lifestyle factors to age-related cognitive decline in adults. Little is known about the potential role of an overall healthy lifestyle in brain structure. We examined the association of adherence to a healthy lifestyle with a panel of brain structural markers among 2,413 participants in PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study in China and 19,822 participants in UK Biobank (UKB). A healthy lifestyle score (0-5) was constructed based on five modifiable lifestyle factors: diet, physical activity, smoking, alcohol consumption, and body mass index. Validated multimodal neuroimaging markers were derived from brain magnetic resonance imaging. In the cross-sectional analysis of PRECISE, participants who adopted four or five low-risk lifestyle factors had larger total brain volume (TBV; ß = 0.12, 95% CI: - 0.02, 0.26; p-trend = 0.05) and gray matter volume (GMV; ß = 0.16, 95% CI: 0.01, 0.30; p-trend = 0.05), smaller white matter hyperintensity volume (WMHV; ß = - 0.35, 95% CI: - 0.50, - 0.20; p-trend < 0.001) and lower odds of lacune (Odds Ratio [OR] = 0.48, 95% CI: 0.22, 1.08; p-trend = 0.03), compared to those with zero or one low-risk factors. Meanwhile, in the prospective analysis in UKB (with a median of 7.7 years' follow-up), similar associations were observed between the number of low-risk lifestyle factors (4-5 vs. 0-1) and TBV (ß = 0.22, 95% CI: 0.16, 0.28; p-trend < 0.001), GMV (ß = 0.26, 95% CI: 0.21, 0.32; p-trend < 0.001), white matter volume (WMV; ß = 0.08, 95% CI: 0.01, 0.15; p-trend = 0.001), hippocampus volume (ß = 0.15, 95% CI: 0.08, 0.22; p-trend < 0.001), and WMHV burden (ß = - 0.23, 95% CI: - 0.29, - 0.17; p-trend < 0.001). Those with four or five low-risk lifestyle factors showed approximately 2.0-5.8 years of delay in aging of brain structure. Adherence to a healthier lifestyle was associated with a lower degree of neurodegeneration-related brain structural markers in middle-aged and older adults.

Association of Serum Cystatin C With Cerebral Small Vessel Disease in Community-Based Population.

BACKGROUND: The aim of this study was to investigate the relationship between serum cystatin C levels and the presence and severity of cerebral small vessel disease (CSVD). METHODS: Community-dwelling residents in the Lishui city in China from the cross-sectional survey of the PRECISE (Poly-Vascular Evaluation for Cognitive Impairment and Vascular Events) cohort study were included in present study from 2017 to 2019. Total CSVD burden and modified total CSVD burden score, as well as the markers of CSVD on magnetic resonance imaging, including white matter hyperintensity, lacunes, cerebral microbleeds, and perivascular spaces, were assessed at baseline survey. Participants were divided into 4 groups according to the quartiles of cystatin C. The association of serum cystatin C with total CSVD burden and imaging markers was analyzed using ordinal or binary logistic regression models. Furthermore, 2-sample Mendelian randomization analysis was performed to investigate the genetically predicted effect of cystatin C on CSVD. RESULTS: A total of 3061 participants were included in this study. The mean age of the participants was 61.2±6.7 years, and 1637 (53.5%) were women. Higher level of cystatin C was associated with an increased total CSVD burden and modified total CSVD burden (Q4 versus Q1: common odds ratio [OR], 1.30 [95% CI, 1.03-1.64] and 1.32 [95% CI, 1.01-1.73]) after adjustment for covariates. Further, compared with the first quartile of cystatin C, subjects in the last quartile had higher risk of lacunes (OR, 1.99 [95% CI, 1.05-3.76]), modified white matter hyperintensity burden (common OR, 1.42 [95% CI, 1.07-1.90]), and moderate-to-severe perivascular spaces (OR, 2.15 [95% CI, 1.29-3.59]) but not cerebral microbleeds. The Mendelian randomization analysis showed that a genetically predicted higher cystatin C level was associated with increased risk of lacunar stroke (OR, 1.16 [95% CI, 1.06-1.27]). CONCLUSIONS: In this community-based study, we found a possible association between cystatin C and CSVD, especially for lacunes, that was independent of estimated glomerular filtration rate.

Effect of Lipoprotein(a) on Stroke Recurrence Attenuates at Low LDL-C (Low-Density Lipoprotein) and Inflammation Levels.

BACKGROUND: Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. METHODS: This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. RESULTS: Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) <50 mg/dL (11.5% versus 9.4%; adjusted HR, 1.20 [95% CI, 1.02-1.42]). However, the risk associated with elevated Lp(a) was attenuated in patients with LDL-Cc <55 mg/dL (high Lp(a) versus low Lp(a): 8.9% versus 9.0%; adjusted HR, 0.92 [95% CI, 0.65-1.30]) or IL-6 <2.65 ng/L (9.0% versus 7.8%; adjusted HR, 1.14 [95% CI, 0.87-1.49]). Notably, in the group with both low LDL-Cc and inflammation levels, the rate of patients with high Lp(a) did not significantly different from the rate of patients with low Lp(a; LDL-Cc <55 mg/dL and IL-6 <2.65 ng/L: 6.2% versus 7.1%; adjusted HR, 0.86 [95% CI, 0.46-1.62]; LDL-Cc <55 mg/dL and hsCRP <2 mg/L: 7.7% versus 7.6%; adjusted HR, 0.97 [95% CI, 0.57-1.66]). However, there was no interaction between the LDL-Cc, IL-6, hsCRP, and Lp(a) levels on stroke recurrence risk. CONCLUSIONS: Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.

Association of inflammatory markers with cerebral small vessel disease in community-based population.

BACKGROUND: This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD). METHODS: A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed. RESULTS: At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05). CONCLUSIONS: This community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

Association between triglyceride glucose index and atherosclerotic plaques and Burden: findings from a community-based study.

BACKGROUND: Insulin resistance is an important cause of cardiovascular events and cerebral infarction development. We aimed to investigate the association of the triglyceride glucose (TyG) index with atherosclerotic burden and plaques in coronary, intra- and extracranial arteries in participants with non-diabetes, and compared the results with that of the homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: Participants without diabetes in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were included. We categorized participants by tertiles of the TyG index and the concordance/discordance of the TyG index and HOMA-IR. Discordance was defined as a TyG index equal to or greater than the median and HOMA-IR less than the median, or vice versa. The atherosclerosis plaques and burden in coronary, intra- and extracranial arteries were evaluated. The association of HOMA-IR and TyG index with the presence of atherosclerotic plaques and atherosclerotic burden was assessed by binary and ordinal logistic regression models, respectively. RESULTS: Among 2,719 included participants, the average age was 60.9 (± 6.6) years, and 53.0% were female. Both TyG index and HOMA-IR were associated with increased odds of coronary/intra- and extracranial atherosclerotic plaques and burden after adjustment for age, sex, currenting smoking and drinking (all P < 0.05). However, the association between HOMA-IR and intracranial atherosclerosis was not statistically significant after adjustment for all potential confounders. Discordantly high TyG index with HOMA-IR had a higher odd of extracranial plaque (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.04-1.71), extracranial atherosclerotic burden (common odds ratio [cOR]: 1.35, 95% CI 1.06-1.71), coronary plaque (OR: 1.30, 95% CI 1.01-1.68) and segment stenosis score (cOR: 1.39, 95% CI 1.09-1.78) as compared with concordantly low TyG index with HOMA-IR. The TyG index had a better net reclassification improvement ability than HOMA-IR for atherosclerotic plaques when adding to baseline model. CONCLUSION: Elevated TyG index was associated with increased odds of atherosclerosis in coronary/intra- and extracranial arteries. Compared with HOMA-IR, the TyG index was more strongly associated with intracranial atherosclerosis. Moreover, discordantly high TyG index with HOMA-IR was also important for atherosclerosis identification.

Validation of the Canadian TIA Score to Predict Subsequent Stroke Risk in Chinese TIA Patients.

BACKGROUND AND OBJECTIVES: The Canadian TIA Score has been verified as a good predictive tool for subsequent stroke risk in Caucasian patients; however, it had insufficient external verification of other races. We aimed to validate the Canadian TIA Score in Chinese patients and compared it with ABCD2 for subsequent stroke risk after transient ischemic attack (TIA). METHODS: The Third China National Stroke Registry (CNSR-III) was a nationwide, multicenter prospective registry recruiting consecutive patients with acute ischemic stroke or TIA within 7 days of the onset from August 2015 to March 2018. The Canadian TIA Score was verified in patients diagnosed with TIA from the CNSR-III (N = 1,184). The outcomes were subsequent stroke at 7 days, 14 days/discharge, 3 months, and 1 year. Outcomes were recorded by face-to-face assessment or telephone interview. The prognostic performance of the scoring system was assessed by the area under the receiver operator characteristic curve (AUC). RESULTS: Of 1,184 TIA patients (mean [IQR] age, 61.00 [53.00-69.00] years; 413 women [34.88%]), there were 40 patients (3.38%) having subsequent stroke within 7 days, 45 (3·80%) within 14 days/hospitalization, 66 (5·57%) within 3 months, and 100 (8·45%) within 1 year. The Canadian TIA Score (AUC 0 63-0·68) seemed to be a better prognostic score of stroke risk than the ABCD2 score (AUC 0·61-0·62), although no significant differences were noted. In the subgroup of atypical TIA, the Canadian TIA Score showed significantly stronger predictivity than the ABCD2 score within 7 days (0.80 [0.62-0.98] vs. 0.52 [0.30-0.73]; difference in AUC, 0.28 [0.03-0.53]; p, 0.026), and marginal significantly stronger predictivity within 1 year (0.71 [0.61-0.80] vs. 0.58 [0.48-0.68]; difference in AUC, 0.12 [-0.01 to 0.25]; p, 0.06). CONCLUSION: The Canadian TIA Score might be a better prognostic score than the ABCD2 score for post-TIA stroke risk, especially in patients with atypical TIA.

Elevated lipoprotein(a) and lipoprotein-associated phospholipase A2 are associated with unfavorable functional outcomes in patients with ischemic stroke.

BACKGROUND: The association of lipoprotein(a) [Lp(a)] and stroke functional outcomes was conflicting. The aim of the study was to clarify whether high Lp(a) is associated with unfavorable functional outcomes in patients with ischemic stroke. METHODS: A total of 9709 individuals from the third China National Stroke Registry cohort were recruited. Plasma level of Lp(a) at admission was measured with enzyme-linked immunosorbent assay. The cut-off was set at the median for Lp(a). Functional outcome was assessed using the modified Rankin scale (mRS) at 3 months and 1 year after ischemic stroke. The association between Lp(a) and functional outcomes was evaluated using a logistic regression model. RESULTS: The median age was 63.0 years, and 31.1% participants were women. Patients in higher Lp(a) group had higher incidences of unfavorable functional outcomes at 3 months. In logistic regression model, elevated Lp(a) levels were associated with unfavorable functional outcomes at 3 months (Q4 vs. Q1: odds ratio 1.33, 95% confidence interval 1.11-1.61). Subgroup analysis showed that in the lower Lp-PLA2 group, Lp(a) level was not associated with functional outcomes, but in the higher Lp-PLA2 group, Lp(a) level was significantly associated with functional outcomes. After grouped by different levels of Lp(a) and Lp-PLA2, the Lp(a) high/ Lp-PLA2 high group showed the highest incidence of unfavorable functional outcomes at 3 months and 1 year. CONCLUSIONS: Elevated Lp(a) level is associated with unfavorable functional outcomes in patients with ischemic stroke. The increment in both Lp(a) and Lp-PLA2 are associated with unfavorable functional outcomes at 3 months and 1 year after ischemic stroke.

Impact of salt substitute and stepwise reduction of salt supply on blood pressure in residents in senior residential facilities: Design and rationale of the DECIDE-Salt trial.

BACKGROUND: High sodium intake has been considered as the leading dietary risk factor for deaths and disability-adjusted life-years among older adults. High-quality randomized trials to evaluate the effects of practical sodium reduction strategies are needed. METHODS: The study is a cluster randomized trial with a 2 × 2 factorial design conducted in 48 senior residential facilities in northern China. These facilities are randomly assigned (1:1:1:1) to 1 of 4 groups: stepwise salt supply control (SSSC) in which 5%-10% of the study salt supply in the institutional kitchens will be reduced every 3 months, replacing normal salt with salt substitute (SS); SSSC only; SS only; or neither SSSC nor SS. The interventions last for 2 years with follow-up every 6 months. The primary outcome is the change in systolic blood pressure from baseline to 24 months. Secondary outcomes include the incidence of hyperkalemia, hyponatremia, cardiovascular events, and death. CURRENT STATUS: The study has recruited and randomized 48 senior residential facilities with 1,606 participants. Mean age at baseline was 71 years, and 76% are male. Both types of salt intervention were initiated in the study facilities between January and April 2018. CONCLUSION: The study is well placed to define the effects of 2 practical and scalable sodium reduction strategies for blood pressure reduction and will provide important new data about safety of these strategies among older adults in China.

The effect of luteal GnRH antagonist on moderate and severe early ovarian hyperstimulation syndrome during in vitro fertilization treatment: a prospective cohort study.

PURPOSE: Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproductive technology (ART) treatment. However, there are limited data regarding the ability of the luteal GnRH antagonist cetrorelix to reduce the incidence of moderate and severe OHSS, and the mechanism remains unclear. Thus, we designed a study to assess the effectiveness of cetrorelix to prevent early moderate and severe OHSS in high-risk patients undergoing controlled ovarian stimulation for IVF/ICSI. METHODS: In this prospective cohort study, 105 patients with high-risk OHSS undergoing cryopreservation of all embryos were divided into two groups according to their personal choice. The cetrorelix group (n = 65) received 0.25 mg of cetrorelix by subcutaneous injection daily, from days 3 to 5 post-oocyte retrieval (POR); the control group (n = 40) received no drug. The primary outcome measures were the incidence and severity of early moderate and severe OHSS. Secondary measures included serum estradiol levels, ovarian volume, ascites volume, hematocrit values, and WBC count on days 3, 6, and 9 POR. VEGF and EGR-1 levels were assessed, and binary logistic regression analysis was applied to predict associations between clinical variables and OHSS. RESULTS: Ninety-six patients were examined. The incidence of moderate and severe OHSS was significantly lower in the cetrorelix group than in the control group (18.03% and 37.14%, respectively; P = 0.037). Serum estradiol (P = 0.013), white blood cell count (P = 0.031), ascites volume (P = 0.036), EGR-1 (P = 0.025), and VEGF levels (P = 0.015) were significantly higher in the control group on day 6 POR than on day 3 POR, while no increase was observed between day 3 POR and day 6 POR in the cetrorelix group, indicating a faster regression of OHSS symptoms. Cetrorelix intervention was associated with the incidence and severity of OHSS (OR 0.29, 95% CI 0.11-0.78, P = 0.014). CONCLUSION: Cetrorelix effectively reduces the incidence of early moderate and severe OHSS in high-risk women and decreases serum VEGF levels.

The 20 Most Important and Most Preventable Health Problems of China: A Delphi Consultation of Chinese Experts.

OBJECTIVES: To identify the 20 most important and most preventable health problems that should be addressed in the next 20 years in China. METHODS: In 2015, we applied a modified electronic Delphi technique to reach consensus from a panel of top Chinese health experts (n = 70), who were requested to identify 20 health problems that, in their judgment, were most important and preventable. We also compared the results with evidences from epidemiological studies on disease-specific mortalities and disability-adjusted life years. RESULTS: Consensus was reached after the second-round survey. The final agreed-upon 20 most important and most preventable health problems included 9 noncommunicable diseases, 4 communicable diseases, 2 unhealthy behaviors, and 2 forms of environmental pollution, plus depression, road injury, and contamination of food with pesticides, antibiotics, and hormone residues. The results are supported by relevant epidemiological studies in China. CONCLUSIONS: The 20 most important and most preventable health problems in China for the next 20 years, agreed upon by a panel of top Chinese health experts, should be taken into consideration in national policymaking.

Incidence, temporal trend and factors associated with ventilator-associated pneumonia in mainland China: a systematic review and meta-analysis.

BACKGROUND: Data to date is far from sufficient to describe the recent epidemiology of ventilator-associated pneumonia (VAP) in mainland China. This study aimed to estimate the overall incidence of VAP, with a special focus on its temporal trend and associated factors. METHODS: Meta-analyses of 195 studies published from 2010 to 2015 were conducted, followed by subgroup analyses by methodological quality, pre-defined setting characteristics and attributes of populations. RESULTS: The overall cumulative VAP incidence in mainland China was 23.8% (95% confidence interval (CI) 20.6-27.2%), with the results showing high heterogeneity. The pooled incidence densities were 24.14 (95% CI 21.19-27.51) episodes and 22.83 (95% CI 19.88-26.23) patients per 1000 ventilator-days. A decline in the cumulative incidence was observed from 2006 (49.5%, 95% CI 40.0-59.0%) to 2014 (19.6%, 95% CI 10.4-31.0%); differences in the incidence rates were also documented according to Chinese provinces and diagnostic criteria (p < 0.001). Older age (≥60 years), coma, re-intubation, tracheotomy and prolonged ventilation were the factors significantly associated with the occurrence of VAP. CONCLUSIONS: The incidence of VAP remains high in mainland China but has decreased since 2006. The reported rates vary considerably across individual studies, probably due to variations in diagnosis and geographical region. More studies using standard definitions and cut-off points are needed to better clarify the epidemiology of VAP across the country.