[Double-column Die-punch fractures of distal radius treated with butterfly plate fixation via Henry approach].

OBJECTIVE: To explore clinical effect of open reduction and internal fixation with Henry's approach butterfly plate in treating double-column Die-punch fractures of distal radius. METHODS: From January 2018 to June 2021, 26 patients with double-column Die-column distal radius were treated with open reduction and internal fixation through Henry's surgical approach and using distal radius volar column plate(butterfly plate), including 14 males and 12 females, aged from 20 to 75 years old with an average age of (44.2±3.4) years old. Postopertaive complications were observed, Gartland-Werley score at 12 months after opertaion was used to evaluate wrist joint function. RESULTS: All 26 patients were followed up from 10 to 18 months with an average of(13.4±0.8) months. All fractures were obtained fracture union, the time ranged from 8.5 to 15.8 weeks with an average of (11.4±0.5) weeks. All incisions healed at stageⅠwithout infection, nerve injury and internal fixation failure occurred. Postoperative Gartland-Werley score at 12 months was (3.65±0.36), and 16 patients got excellent result, 8 good and 2 moderate. CONCLUSION: Open reduction and internal fixation with butterfly plate for the treatment of double-column Die-punch fractures of the distal radius through volar Henry approach could obtain satisfactory clinical outcomes.

The Ocean Carbon and Acidification Data System.

The Ocean Carbon and Acidification Data System (OCADS) is a data management system at the National Oceanic and Atmospheric Administration (NOAA) National Centers for Environmental Information (NCEI). It manages a wide range of ocean carbon and acidification data, including chemical, physical, and biological observations collected from research vessels, ships of opportunity, and uncrewed platforms, as well as laboratory experiment results, and model outputs. Additionally, OCADS serves as a repository for related Global Ocean Observing System (GOOS) biogeochemistry Essential Ocean Variables (EOVs), e.g., oxygen, nutrients, transient tracers, and stable isotopes. OCADS endeavors to be one of the world's leading providers of ocean carbon and acidification data, information, products, and services. To provide the best data management services to the ocean carbon and acidification research community, OCADS prioritizes adopting a customer-centric approach and gathering knowledge and expertise from the research community to improve its data management practices. OCADS aims to make all ocean carbon and acidification data accessible via a single portal, and welcomes submissions from around the world: https://www.ncei.noaa.gov/products/ocean-carbon-acidification-data-system/.

Exploring the Value of Radiomics Features Based on B-Mode and Contrast-Enhanced Ultrasound in Discriminating the Nature of Thyroid Nodules.

BACKGROUND: With the improvement of ultrasound imaging resolution and the application of various new technologies, the detection rate of thyroid nodules has increased greatly in recent years. However, there are still challenges in accurately diagnosing the nature of thyroid nodules. This study aimed to evaluate the clinical application value of the radiomics features extracted from B-mode ultrasound (B-US) images combined with contrast-enhanced ultrasound (CEUS) images in the differentiation of benign and malignant thyroid nodules by comparing the diagnostic performance of four logistic models. METHODS: We retrospectively collected and ultimately included B-US images and CEUS images of 123 nodules from 123 patients, and then extracted the corresponding radiomics features from these images respectively. Meanwhile, a senior radiologist combined the thyroid imaging reporting and data system (TI-RADS) and the enhancement pattern of the ultrasonography to make a graded diagnosis of the malignancy of these nodules. Next, based on these radiomics features and grades, logistic regression was used to help build the models (B-US radiomics model, CEUS radiomics model, B-US+CEUS radiomics model, and TI-RADS+CEUS model). Finally, the study assessed the diagnostic performance of these radiomics features with a comparison of the area under the curve (AUC) of the receiver operating characteristic curve of four logistic models for predicting the benignity or malignancy of thyroid nodules. RESULTS: The AUC in the differential diagnosis of the nature of thyroid nodules was 0.791 for the B-US radiomics model, 0.766 for the CEUS radiomics model, 0.861 for the B-US+CEUS radiomics model, and 0.785 for the TI-RADS+CEUS model. Compared to the TI-RADS+CEUS model, there was no statistical significance observed in AUC between the B-US radiomics model, CEUS radiomics model, B-US+CEUS radiomics model, and TI-RADS+CEUS model (P>0.05). However, a significant difference was observed between the single B-US radiomics model or CEUS radiomics model and B-US+CEUS radiomics model (P<0.05). CONCLUSION: In our study, the B-US radiomics model, CEUS radiomics model, and B-US+CEUS radiomics model demonstrated similar performance with the TI-RADS+CEUS model of senior radiologists in diagnosing the benignity or malignancy of thyroid nodules, while the B-US+CEUS radiomics model showed better diagnostic performance than single B-US radiomics model or CEUS radiomics model. It was proved that B-US radiomics features and CEUS radiomics features are of high clinical value as the combination of the two had better diagnostic performance.

Novel and disappearing climates in the global surface ocean from 1800 to 2100.

Marine ecosystems are experiencing unprecedented warming and acidification caused by anthropogenic carbon dioxide. For the global sea surface, we quantified the degree that present climates are disappearing and novel climates (without recent analogs) are emerging, spanning from 1800 through different emission scenarios to 2100. We quantified the sea surface environment based on model estimates of carbonate chemistry and temperature. Between 1800 and 2000, no gridpoints on the ocean surface were estimated to have experienced an extreme degree of global disappearance or novelty. In other words, the majority of environmental shifts since 1800 were not novel, which is consistent with evidence that marine species have been able to track shifting environments via dispersal. However, between 2000 and 2100 under Representative Concentrations Pathway (RCP) 4.5 and 8.5 projections, 10-82% of the surface ocean is estimated to experience an extreme degree of global novelty. Additionally, 35-95% of the surface ocean is estimated to experience an extreme degree of global disappearance. These upward estimates of climate novelty and disappearance are larger than those predicted for terrestrial systems. Without mitigation, many species will face rapidly disappearing or novel climates that cannot be outpaced by dispersal and may require evolutionary adaptation to keep pace.

GDF11 Alleviates Pathological Myocardial Remodeling in Diabetic Cardiomyopathy Through SIRT1-Dependent Regulation of Oxidative Stress and Apoptosis.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in diabetic cardiomyopathy (DCM) remain largely unknown. In this study, we sought to determine whether GDF11 could prevent DCM. After establishing a mouse model of diabetes by administering a high-fat diet and streptozotocin, intramyocardial injection of an adeno-associated virus was used to achieve myocardium-specific GDF11 overexpression. GDF11 remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression and activity were observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were eliminated by SIRT1 depletion. Our results demonstrate for the first time that GDF11 protects against DCM by regulating SIRT1 signaling pathway.

Controls on surface water carbonate chemistry along North American ocean margins.

Syntheses of carbonate chemistry spatial patterns are important for predicting ocean acidification impacts, but are lacking in coastal oceans. Here, we show that along the North American Atlantic and Gulf coasts the meridional distributions of dissolved inorganic carbon (DIC) and carbonate mineral saturation state (Ω) are controlled by partial equilibrium with the atmosphere resulting in relatively low DIC and high Ω in warm southern waters and the opposite in cold northern waters. However, pH and the partial pressure of CO2 (pCO2) do not exhibit a simple spatial pattern and are controlled by local physical and net biological processes which impede equilibrium with the atmosphere. Along the Pacific coast, upwelling brings subsurface waters with low Ω and pH to the surface where net biological production works to raise their values. Different temperature sensitivities of carbonate properties and different timescales of influencing processes lead to contrasting property distributions within and among margins.

Surface ocean pH and buffer capacity: past, present and future.

The ocean's chemistry is changing due to the uptake of anthropogenic carbon dioxide (CO2). This phenomenon, commonly referred to as "Ocean Acidification", is endangering coral reefs and the broader marine ecosystems. In this study, we combine a recent observational seawater CO2 data product, i.e., the 6th version of the Surface Ocean CO2 Atlas (1991-2018, ~23 million observations), with temporal trends at individual locations of the global ocean from a robust Earth System Model to provide a high-resolution regionally varying view of global surface ocean pH and the Revelle Factor. The climatology extends from the pre-Industrial era (1750 C.E.) to the end of this century under historical atmospheric CO2 concentrations (pre-2005) and the Representative Concentrations Pathways (post-2005) of the Intergovernmental Panel on Climate Change (IPCC)'s 5th Assessment Report. By linking the modeled pH trends to the observed modern pH distribution, the climatology benefits from recent improvements in both model design and observational data coverage, and is likely to provide improved regional OA trajectories than the model output could alone, therefore, will help guide the regional OA adaptation strategies. We show that air-sea CO2 disequilibrium is the dominant mode of spatial variability for surface pH, and discuss why pH and calcium carbonate mineral saturation states, two important metrics for OA, show contrasting spatial variability.

Coral Reefs and People in a High-CO2 World: Where Can Science Make a Difference to People?

REEFS AND PEOPLE AT RISK: Increasing levels of carbon dioxide in the atmosphere put shallow, warm-water coral reef ecosystems, and the people who depend upon them at risk from two key global environmental stresses: 1) elevated sea surface temperature (that can cause coral bleaching and related mortality), and 2) ocean acidification. These global stressors: cannot be avoided by local management, compound local stressors, and hasten the loss of ecosystem services. Impacts to people will be most grave where a) human dependence on coral reef ecosystems is high, b) sea surface temperature reaches critical levels soonest, and c) ocean acidification levels are most severe. Where these elements align, swift action will be needed to protect people's lives and livelihoods, but such action must be informed by data and science. AN INDICATOR APPROACH: Designing policies to offset potential harm to coral reef ecosystems and people requires a better understanding of where CO2-related global environmental stresses could cause the most severe impacts. Mapping indicators has been proposed as a way of combining natural and social science data to identify policy actions even when the needed science is relatively nascent. To identify where people are at risk and where more science is needed, we map indicators of biological, physical and social science factors to understand how human dependence on coral reef ecosystems will be affected by globally-driven threats to corals expected in a high-CO2 world. Western Mexico, Micronesia, Indonesia and parts of Australia have high human dependence and will likely face severe combined threats. As a region, Southeast Asia is particularly at risk. Many of the countries most dependent upon coral reef ecosystems are places for which we have the least robust data on ocean acidification. These areas require new data and interdisciplinary scientific research to help coral reef-dependent human communities better prepare for a high CO2 world.

[Preliminary report of using cardiopulmonary exercise testing guide exercise rehabilitation in patients with chronic heart failure].

OBJECTIVE: The exercise rehabilitation in patient with chronic heart failure (CHF) is standard clinical practice, but it is rare using CardioPulmonary Exercise Testing (CPET) guide to prescribe exercise rehabilitation in China. METHODS: We performed symptom limited maximal CPET in 10 patients with CHF, randomly divided into two groups: 5 patients as control without exercise and 5 exercise patients used Δ50%W intensity to exercise 30 min/d, 5 d/w, x12 w. Before and after 12 w rehabilitation, we evaluated functions. RESULTS: There were no significant difference between two groups patients (P > 0.05). The exercise duration was increased from 8 min to 23 min after rehabilitation (P < 0.001); distance 6 minutes walking was increased from 394 m to 470 m (P < 0.05); score of Minnesota quality of life was decreased from 25 to 3 in exercise group (P < 0.01). However, there were nosignificant changes in control group (P>0.05) and their changes were smaller than those in exercise group (P < 0.01). CONCLUSION: The CPET guiding exercise rehabilitation is safe and effective for patients with CHF.

[Effect of valsartan on cyclooxygenase-2 expression in cultured human umbilical vein endothelial cells stimulated by ox-LDL].

OBJECTIVE: To investigate the effects of valsartan on cyclooxygenase-2 (COX-2) in cultured human umbilical vein endothelial cells (HUVECs) stimulated by ox-LDL. METHODS: HUVECs were cultured in endothelial basal medium and divided into four groups (n = 5 each): group I, control group without any treatment; group II: HUVECs stimulated with ox-LDL (100 mg/L) in endothelial basal medium for 24 hours; group III: HUVECs treated with ox-LDL (100 mg/L) and valsartan (10 µmol/L) in endothelial basal medium for 24 hours; group IV: HUVECs treated with ox-LDL (100 mg/L) and valsartan (30 µmol/L) in endothelial basal medium for 24 hours. Expression of COX-1 and COX-2 mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Expression of and COX-2 mRNA was significantly higher in ox-LDL-treated HUVECs than in control group (1.478 ± 0.104 vs. 0.366 ± 0.104, P < 0.05), while expression of COX-1 mRNA was similar between the 2 groups (P > 0.05). Valsartan dose-dependently decreased the COX-2 mRNA expression (group III vs. group II: 1.074 ± 0.112 vs. 1.478 ± 0.104, P < 0.05; group IV vs. group II: 0.664 ± 0.104 vs. 1.478 ± 0.104, P < 0.05). Expression of COX-1 mRNA in ox-LDL-treated HUVECs was not affected by valsartan. CONCLUSIONS: COX-2 mRNA expression in ox-LDL-treated HUVECs could be reduced by valsartan suggesting valsartan might attenuate atherosclerosis by reducing ox-LDL-induced inflammatory responses.

[Study on the relationship between partial deletions in the azzospermia factor C region of Y chromosome and male infertility].

OBJECTIVE: To investigate the relationship between the partial deletions in the azzospermia factor(AZFc) region of Y chromosome and male infertility. METHODS: Multiplex PCR technology was performed to screen the partial deletions in the AZFc region in 158 azoospermia, 160 severe oligozoospermia and 135 oligozoospermia patients and 236 men with normal spermatogenesis.For samples with gr/gr, b2/b3 recombinogenic deletions, author applied RFLP method to identify which DAZ gene doublet deletion was involved. RESULTS: The gr/gr and b2/b3 were two types of common deletions detected. There were significant differences in the b2/b3 deletion in patients with oligozoospermia and severe oligozoospermia compared to the controls (both P< 0.05). However, there was no difference for the gr/gr deletion between the patients and controls. CONCLUSION: The results suggested that the b2/b3 deletion might be a risk factor to spermatogenic impairment and might lead to male infertility.

[The randomized study of efficiency and safety of antithrombotic therapy in nonvalvular atrial fibrillation: warfarin compared with aspirin].

OBJECTIVE: To investigate whether warfarin is more effective and superior to aspirin for the prevention of thromboembolism in nonvalvular atrial fibrillation in Chinese. METHODS: In a multicenter randomized trial, the patients diagnosed as nonvalvular atrial fibrillation were randomized to receive aspirin 150 mg - 160 mg once daily or adjusted-dose warfarin (international normalized ratio, 2.0 - 3.0). We compared the effect of the two therapy on the primary end point of ischemic stroke or death from any cause and on the combined end-point (stroke, death, peripheral arteries embolism, TIA, acute myocardial infarction, serious bleeding) during a median follow-up period of 19 months. RESULTS: Of the 704 patients, 420 (59.7%) were male. The average patient age was (63.3 +/- 9.9) years. The median follow-up period is 19 months. The mean dose of warfarin was (3.2 +/- 0.7) mg. Compared with aspirin, the primary end point of death or ischemic stroke was reduced by warfarin (2.7% vs 6.0%, P = 0.03, OR 0.44, 95% CI 0.198 - 0.960) and the relative risk decreased by 56%. The thromboembolism event in the aspirin group was significantly higher than that in warfarin group (10.6% vs 5.4%, P = 0.01, OR 0.48, 95% CI 0.269 - 0.858). There was no significant differences of the mortality rate between the two groups (1.2% vs 2.2%, P > 0.05). The secondary end point was nonsignificantly reduced in warfarin group than that in aspirin group, while the combined end point is statistically decreased by adjusted-dose warfarin (8.4% vs 13.0%, P = 0.047). Warfarin treatment was associated with increased bleeding rate compared to aspirin (6.9% vs 2.4%, P < 0.05), although the major bleeding rate is rather low (1.5%). All the major bleeding events occurred with INR above 3.0. CONCLUSIONS: Randomized control study demonstrated that anticoagulation with adjusted-dosed warfarin (INR 2.0 - 3.0) can significantly reduced the risk of thromboembolism event with slightly increased hemorrhage, compared to aspirin in Chinese population. Under intensive monitoring, warfarin is effective and safe for the moderate to high risk atrial fibrillation patients.

[The relationship between TIMI (thrombolysis in myocardial infarction) risk score and efficacy of conservative or interventional strategy in patients with non-ST-segment elevation acute coronary syndromes].

OBJECTIVE: To investigate the relationship between thrombolysis in myocardial infarction (TIMI) risk score and efficacy of different treatment strategies in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). METHODS: From Oct. 2001 to Oct. 2003, 545 consecutive patients with NSTE-ACS were randomly assigned to early conservative strategy (n = 284) or early invasive strategy group (n = 261). The combined cardiovascular events (a combination of cardiac death, nonfatal myocardial infarction, nonfatal heart failure and re-hospital admission due to recurrent ischemia angina) within 30 days and 6 months were analyzed and related to the TIMI risk score at admission. RESULTS: Rehospitalization due to recurrent ischemia angina of 30 days and the combined cardiovascular events of 30 days and 6 months were significantly lower in early invasive strategy group (3.5%, 10.0%, 21.1%) compared with early conservative strategy group (8.1%, 16.9%, 28.2%, all P < 0.05). Subgroup analysis indicated early invasive strategy could significantly decrease the 30 d incidence of the combined end point events in patients with high TIMI risk score and the 6 months incidence of the combined end point events in patients with moderate and high TIMI risk score (all P < 0.01), but the incidence was similar between the two different strategies in patients with low TIMI risk score. CONCLUSIONS: Early invasive strategy may significantly reduce combined cardiovascular events in NSTE-ACS patients with moderate and high TIMI risk score compared with early conservative strategy.

[The effect of early invasive strategy on early and late outcomes in high-risk non-ST-segment elevation acute coronary syndromes].

OBJECTIVE: To investigate the effect of early invasive strategy on early and late outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes (ACS). METHODS: Five hundred and forty-five patients of ACS without ST-segment elevation were randomly assigned to an early conservative strategy (284 cases) or early invasive strategy group (261 cases), who were enrolled consecutively from Oct., 2001 to Oct., 2003. The combined cardiovascular events (a combination of cardiac death, nonfatal myocardial infarction, nonfatal heart failure and hospital readmission due to recurrent ischemic angina) within 30 days and 6 months were analyzed and the effects of early invasive strategy on early and late outcomes in high-risk patients with increased TnI or hs-CRP levels were evaluated. RESULTS: As compared with early conservative strategy, early invasive strategy lowered the rate of hospital readmission due to recurrent ischemic angina of 30 d and the combined cardiovascular events of 30 d and 6 months (all P < 0.05). Subgroup analysis indicated early invasive strategy could significantly decrease the incidences of the combined cardiovascular events of 30 d and 6 months and the hard end point events of 6 months in patients with increased TnI or hs-CRP levels (all P < 0.01), but no such changes could be seen in patients with normal TnI or hs-CRP levels, as compared with early conservative strategy. CONCLUSIONS: Early invasive strategy decreases significantly cardiovascular events and improves the early and late outcomes in high-risk patients with increased TnI or hs-CRP levels.

[Predictive value of positive troponin I in clinical prognosis of non-ST-segment elevation acute coronary syndrome].

OBJECTIVE: To investigate the predictive value of positive troponin I (TnI) on early prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS), and to evaluate TnI as a predictor of risk for the combined end points of cardiac events in NSTE ACS. METHODS: 545 patients with non-ST-elevation acute coronary syndrome were double-blind randomly enrolled in two groups of study, receiving invasive or noninvasive treatment, respectively. At admission, all patients' baseline levels of TnI and CK-MB were determined and related to outcome at 30th day and 6th month of follow-up. Aspirin, beta-blocker, ACEI and LWMH were given depending on patients' clinical condition. RESULTS: After a follow up of 6 months, hospitalization because of recurrent angina pectoris and combined end points of cardiac events in TnI positive patients occurred much more as compared with that in the TnI negative patients and the prognosis improved with early invasive interventional treatment strategy in the TnI positive patients (P < 0.01) at 30th day and 6th month. For TnI negative patients, there was no difference between the two groups whether invasive or non-invasive therapy was given. CONCLUSIONS: There is high recurrence rate of angina pectoris and increased number of combined end points of cardiac events in positive TnI patients during follow-up period. TnI served as an important risk factor in NSTE ACS patients and active early invasive intervention therapy should be the first choice for TnI positive patients, but it makes no more benefits for TnI negative patients.

[The changes of electrocardiogram and impact of early invasive strategy in patients with acute coronary syndromes without ST-segment elevation].

OBJECTIVE: To investigate the changes of electrocardiogram (ECG) and impact of early invasive strategy in patients with acute coronary syndrome (ACS) without ST-segment elevation. METHODS: Five hundred and forty-five consecutive ACS patients without ST-segment elevation were randomly assigned to early conservative treatment group and early invasive treatment group. The combined cardiovascular events, including cardiac death, nonfatal myocardial infarction, nonfatal heart failure, and re-hospitalization due to recurrent ischemia angina, within 30 days and 6 months were analyzed and the effects of varied ECG changes and different intervention strategies on outcomes of patients were evaluated. RESULTS: The incidences of each and combined cardiovascular events were higher in the patients with ST-segment depression than in those without ST-segment depression. ST-segment depression was one of independent predictive factors for an increase in cardiovascular events within 6 months (OR 3.864, 95% CI: 1.668 approximately 9.451, P < 0.001). Early invasive strategy was associated with a lower rate of re-hospitalization due to recurrent ischemia angina within 30 days and a decreased incidence of combined cardiovascular events within 30 days and 6 months in comparison with the early conservative treatment group (all P < 0.05). Subgroup analysis implied that incidences of combined cardiovascular events within 30 days and 6 months decreased significantly only in patients with ST-segment depression treated with early invasive strategy, and no such benefit was seen in the patients without ST-segment depression. CONCLUSION: ST-segment depression is an effective indicator for identifying those patients with non-ST segment elevation ACS most likely to benefit from early invasive strategy. Early invasive strategy markedly decreases the cardiovascular events in ACS patients with ST-segment depression than early conservative strategy.

[The studies of risk factors and early intervention in patients with acute coronary syndromes without ST-segment elevation].

OBJECTIVE: To investigate the risk factors and the values of early invasive intervention in patients with acute coronary syndromes (ACS) without ST-segment elevation. METHODS: Five hundred and forty-five patients of ACS without ST-segment elevation were randomly assigned to an early conservative strategy or early invasive strategy who had been admitted to hospitals consecutively from Oct. 2001 to Oct. 2003. The combined cardiovascular events (a combination of cardiac death, nonfatal myocardial infarction, nonfatal heart failure and re-hospital admission due to recurrent ischemia angina) within 30 days and 6 months were analyzed and the primary high risk factors for combined cardiovascular events were evaluated by means of multivariate logistic regression analysis among baseline clinical characteristics and laboratory data, meanwhile, the effects of an early conservative strategy or early invasive strategy on outcomes were also investigated. RESULTS: The incidences of combined cardiovascular events within 30 days and 6 months among 513 cases were 14.0% and 25.7% respectively. Multivariate logistic regression analysis implied ST-segment depression, elevation of troponin I level, increased C-reactive protein, lower ejection fraction of left ventricular and higher TIMI risk scores were all associated with an increases in cardiovascular events within 6 months, and they were respectively independent predictive factor for the increases of cardiovascular events. Early invasive strategy was associated with a lower rate of re-hospital admission due to recurrent ischemia angina within 30 days and a decreased incidences of combined cardiovascular events within 30 days and 6 months compared with early conservative strategy (all P < 0.05). CONCLUSIONS: ST-segment depression, elevation of troponin I level, increased C-reactive protein, lower ejection fraction of left ventricular and higher TIMI risk scores are high risk factors for patients with ACS without ST-segment elevation, and early invasive strategy can have a substantial impact in reducing combined cardiovascular events.