Compounds from olive (Olea europaea L.) and pomegranate (Punica granatum L.) have many beneficial effects on human health. This review paper considers the inhibitory potential, under in vitro conditions, of bioactive components of olive and pomegranate on different enzyme systems. Research shows that olive polyphenols (oleuropein, hydroxytyrosol, luteolin, and oleocanthal), as well as pomegranate polyphenols (punicalagin, urolithin A, ellagic acid), inhibit cyclooxygenase and lipoxygenase enzymes, which are associated with inflammatory processes. They also show an inhibitory effect on acetylcholinesterase, butyrylcholinesterase, and β-secretase, which opens up the possibility of a strong neuroprotective effect. Olive and pomegranate polyphenols also have an inhibitory effect on enzymes involved in carbohydrate metabolism, such as amylase and glucosidase, and can help fight diabetes and regulate human metabolism. In addition, polyphenols and extracts of both plants showed an inhibitory effect on cytochrome P450 enzymes, which metabolize most drugs. These data open up the possibility of interactions with certain groups of drugs. The current evidence supports the view that olive and pomegranate polyphenols act as biologically versatile compounds with considerable pharmaceutical and nutraceutical potential. Future investigations integrating enzymology, metabolomics, molecular docking, and clinical validation will be essential for translating these promising in vitro findings into evidence-based therapeutic applications.

Acute coronary syndrome (ACS) is increasingly prevalent among young patients. The prevalence of ACS among young women has also increased. It is well known that coronary artery disease (CAD) follows a different pattern in women and men. In order to provide timely and appropriate treatment, it is necessary to understand the gender differences in the risk factors, clinical profile, and early outcome in the young ACS patient population. Understanding and addressing the risk factors linked to the early onset of the disease is therefore essential to lowering the burden of premature CAD (PCAD). This study aimed to analyse the gender differences in the presence of major coronary risk factors, clinical presentation, diagnosis and immediate outcomes in patients with PCAD. We evaluated 218 consecutive patients who were hospitalised in the ICCU of cardiology department with diagnosis of PCAD between November 2023 and May 2025, after satisfying the inclusion criteria. All included patients were 45 years of age or younger, were admitted for their first acute coronary syndrome and underwent primary PCI with optimal revascularization results. The study included 72 female and 146 male patients. The mean age of females was 42.5 ± 2.22 years and males was 39.6 ± 3.85 years (p<0.001). Young women had significantly more risk burden of hypertension (70.2% vs 36.5% p<0.001) diabetes (38.9% vs 28.7%, p<0.001) and dyslipidaemia (61.4% vs. 38.4%, p<0.001) compared to young men. Among young males, smoking was significantly higher (76.5% vs. 25.2%, p<0.001). NSTEMI was more common presentation among females (22.5% vs 8.4%, p<0.001) with more prevalent non obstructive CAD (13.1% vs. 8.2%, p=0.15). Young male patients showed angiographically more severe CAD and greater frequency of multivessel CAD (22.8% vs 17.9%, p=0.58). Young female patients had significantly better mean ejection fraction (EF) (48.1±7.9% vs 39.2±9.8%, p=0.13). Young women had more often acute heart failure (Kilip class ≥ 2) and longer length of stay in the intensive care unit (12.4% vs.6.29%, P=0.04; 5.5 vs 2.7 days, p <0.001 respectively). Mortality rate in the first 48 hours of admission was higher in man than in woman (1.65% vs.1.13%, p=0.65). A distinct gender difference in the risk factor profile for PCAD supports an early, comprehensive, but gender-specific approach to prevention. Young patients with premature CAD may benefit from these findings in terms of risk factor modification and gender-based management approach.

Atherosclerosis is a progressive vascular disease characterized by lipid-rich plaque accumulation, oxidative stress, and chronic inflammation, contributing to coronary heart disease, stroke, and peripheral arterial disease. This study investigated the impact of inflammation, vascular calcification, and statin therapy on redox balance in blood and carotid artery plaques, aiming to identify potential biomarkers for disease assessment. Thirty-two patients undergoing carotid endarterectomy provided 34 plaque samples. Enzyme activities in plaque/erythrocytes and –SH group concentration in plasma/plaque were measured. Pathological analysis was performed to determine inflammation/calcification grade, the presence of mast cells and plaque composition. The results showed that mast cells were associated with reduced non-protein –SH groups, indicating selective thiol consumption and serving as a qualitative marker of oxidative burden. Reduced catalase activity in erythrocytes was associated with advanced calcification, pointing to long-standing systemic oxidative stress. Statin therapy enhanced systemic superoxide-dismutase 1 activity, increased –SH groups, and modulated plaque-specific glutathione reductase activity, attenuating sex-related differences in redox regulation. These findings highlight the complex interplay between systemic and local oxidative processes in atherosclerosis through alterations in redox-related biomarkers such as plasma –SH group concentrations and catalase activity.

In the realm of preventive medicine, reinforcement of a zero-tolerance stance on cigarette smoking is imperative. The use of heat-not-burn (HnB) technology by individuals who are unable to quit smoking has prompted strong discussions in both the public health and clinical domains. This raises the question of whether exposure to cigarettes or HnB products has a different effect on blood pressure (BP) values and whether this effect depends on the concentration of heavy metals. A total of 33 participants were divided into four exposure groups: passive HnB exposure (n=7), active HnB users (n=4), passive cigarette smokers (n=11), and active cigarette smokers (n=9). Blood concentrations of cadmium (Cd) and lead (Pb) were determined by atomic absorption spectroscopy (AAS) using a Graphite Furnace Atomic Absorption Spectrometer, Agilent 240Z AA (Agilent Technologies, Santa Clara, CA, USA). Samples were prepared by wet digestion with nitric acid solution. After centrifugation, the supernatant was transferred into vials for AAS analysis. Concentrations of Cd and Pb were measured before and after exposure, and changes were analyzed using generalized linear models (GLM) adjusted for sex, age, and body mass index (BMI). All participants were smokers who had stopped smoking five days prior to the experiment. None of the participants had any chronic diseases. After a five-day abstinence (washout period), they were exposed to active and passive consumption of HnB or traditional cigarettes. BP was measured before and after exposure to tobacco smoke. Average Cd levels were similar across all groups (p = 0.55): passive HnB 1.59 µg/L, active HnB 1.29 µg/L, passive cigarette smokers 1.65 µg/L, and active cigarette smokers 1.64 µg/L. Pb levels varied significantly by exposure type (p = 0.006), as follows: 35.95 µg/L with passive HnB exposure, 26.98 µg/L with active HnB exposure, 52.45 µg/L and 36.50 µg/L in passive and active cigarette smokers, respectively. Upon monitoring, an elevation in Cd levels was significantly associated with a rise in systolic pressure (p = 0.026) and a decrease in diastolic pressure (p = 0.006), indicating an increase in pulse pressure and potential arterial stiffness. Pb concentration showed no direct effect on hemodynamic parameters. These findings suggest that Cd and Pb levels vary based on type of exposure. There was a significant difference between traditional cigarettes and HNB products, with the latter exhibiting lower concentrations, as well as between active and passive exposure. Changes in BP tend to be more closely linked to Cd, as higher levels correlate with increased systolic and decreased diastolic pressures, indicating its role in arterial stiffness and early vascular dysfunction.

Aim To investigate integrated biochemical and glycomic signatures in humans related to coordinated metabolic and endocrine adaptations during prolonged fasting, which are essential for maintaining systemic homeostasis. Methods This single-arm longitudinal interventional study enrolled five healthy adults who underwent a 72-hour water-only fast. Blood samples were collected at baseline (T0), immediately after fasting (T1), and after 11 days of refeeding (T2). A broad panel of biochemical, hormonal, inflammatory, and glycomic parameters was determined. Time-dependent differences were evaluated using the Friedman test. Results Fasting induced a distinct biphasic response across multiple circulating markers, with significant alterations in total cholesterol, C-reactive protein, thyroid-stimulating hormone, and free triiodothyronine at T1 followed by recovery toward baseline at T2. Insulin and glucose concentrations declined during fasting and increased after refeeding, although these changes did not reach statistical significance. Plasma, immunoglobulin G (IgG), and IgA N-glycosylation profiles were extensively remodeled, which indicated dynamic metabolic and immune system adaptation. Liver enzymes, electrolytes, and most lipid fractions exhibited only minor and reversible fluctuations. Conclusion A 72-hour fast was associated with metabolic and hormonal changes consistent with an environment conducive to autophagy, although autophagy was not measured directly. The protocol appeared feasible and well tolerated in a small cohort of healthy adults. Given the limited sample size, these findings should be considered preliminary and require confirmation in larger studies incorporating direct autophagy markers and additional time points.

This case report presents an updated interpretation of genetic and chronological data from human remains discovered in Bezdanjača Cave, a Bronze Age burial site located in the Lika region of Croatia. The cave contains a complex necropolis with at least 57 graves and up to 200 individuals, which indicates its use as a collective burial site during the Middle and Late Bronze Age. Based on ancient DNA analysis, 13 males were identified among 38 analyzed individuals, with the majority belonging to the Y-chromosome haplogroup R1b, commonly associated with Bronze Age populations. However, two individuals were assigned to haplogroup I2a1a (I-Y3120). The I2a lineage has deep roots in Europe, and its presence has been confirmed in prehistoric contexts in Croatia and the region. However, newly obtained radiocarbon dates from occipital bones reveal that at least one of the two I2a1a individuals from Bezdanjača Cave dates to the Early Modern period (1645-1950 calibrated CE), which indicates that the remains were deposited in the cave much later than previously assumed. At the same time, these new data do not contradict the possible presence of the I2a1a lineage in Bronze Age populations in this area, as Bronze Age I2a1a samples have been reported from other archaeological sites in Croatia and the wider region. These findings, presented here for the first time, highlight the risks of assuming chronological homogeneity based solely on archaeological context and demonstrate the necessity of direct radiocarbon dating when integrating archaeological and genetic data. An interdisciplinary approach and careful chronological verification in ancient DNA research are essential to avoid misinterpretations in broader population genetic studies.

Commercially available graphene quantum dots (GQDs) are promising nanomaterials for applications in research and preclinical diagnostics, drug delivery, and bioimaging. Their bioactivity is highly dependent on dose, route of exposure, duration, cell type, uptake mechanisms, tissue and cellular distribution, and physicochemical properties. This study aimed to evaluate genotoxic, cytotoxic, and cytostatic endpoints of blue- (B-GQDs) and green-emitting (G-GQDs) GQDs in human blood and salivary leukocytes. GQDs were tested at concentrations ranging from 2.5 to 100 µg/mL using distinct treatment periods. Fourier transform infrared spectroscopy (FTIR), trypan blue exclusion, comet, and cytokinesis-block micronucleus cytome (CBMN cyt) assays were performed. FTIR analysis revealed that G-GQDs, unlike B-GQDs, exhibit an absorption band typically associated with amine functional groups, which may contribute to their pronounced genotoxic effects. Peripheral blood mononuclear cells and salivary leukocytes showed higher sensitivity to G-GQDs compared to whole blood samples. Although no cytotoxic effects were observed, both GQDs induced significant DNA damage, with G-GQDs demonstrating greater genotoxic potential. These findings demonstrate that GQDs can induce DNA damage in the absence of detectable cytotoxic effects under the conditions tested, highlighting the importance of considering both physicochemical properties and cellular models in the safety assessment of nanomaterials.

Modern football is characterized by playing both in defense and attack, which requires greater energy demands from players, and the amount and intensity of movement increases from year to year. The aim of the study was to determine differences in the distance covered and movement intensities of players in relation to their position in the team. The sample was players who played all 90 minutes of the knockout phase of the 2022 World Cup (N=224), according to positions: goalkeepers (n=31), defense (n=101), midfielders (n=61), and attackers (n=31). Data were taken from the official FIFA website (www.fifa.com): distance covered (m), distance covered in zone 1 (speed 0-7 km/h), in zone 2 (7-15 km/h), in zone 3 (15-20 km/h), in zone 4 (20-25 km/h) and in zone 5 (>25 km/h), number of runs in zone 4, number of sprints in zone 5, maximum achieved speed (km/h). Differences between positions were determined by discriminant analysis. Three discriminant functions were isolated that are statistically significant at the 99% level (sig.=0.000) (Can. Cor.=0.934; Can. Cor =0.492 and Can. Cor.=0.356). The highest correlations with the first function, which maximally differentiates positions (Wilks Lambda =0.085; sig.=0.000), have the variables: intensity of movement in zone 2, number of runs in zone 4 and total distance covered. The second function (Wilks Lambda =0.662; sig.=0.000) is determined by the maximum achieved speed and distance covered in zone 3. The third function (Wilks Lambda =0.873; sig.0.000) is determined by intensity of movement in zone 4, number of sprints, distance covered in zone 5 and in zone 1. Excluding the goalkeeper position, it is evident that positions in the team are approaching each other in relation to distance covered, intensity of movement and maximum speed of movement, which supports the thesis that in modern football, polyvalent football players who can be used in multiple positions in the team are increasingly profiled

Unergative verbs assign the agent theta role to subjects whereas unaccusative verbs occur with theme subjects. Theory suggests that, unlike subjects of unergative verbs, theme subjects of unaccusative verbs are merged in the post-verbal internal argument position and moved to the pre-verbal external argument position. In a cross-modal lexical priming experiment, we tracked (re‑)activation patterns of the subject in sentences with imperfective and perfective unergative and unaccusative verbs in Bosnian/Croatian/Serbian (BCS). We investigated the interplay between unaccusativity and verbal aspect. Our findings are that the subject of perfective unaccusative verbs is (re‑)activated post-verbally, at the gap position, whilst this is not the case for unergative verbs and imperfective unaccusative verbs.

Pomegranate peel, an abundant agro-industrial by-product, represents a sustainable source of bioactive polyphenols, particularly punicalagin, which has been associated with antioxidant and photoprotective potential. This study aimed to develop microemulsions (MEs) containing pomegranate peel extract for dermal delivery of punicalagin using biocompatible surfactant systems. Three MEs differing in surfactant–cosurfactant composition (ME-A, ME-P, and ME-E) were prepared. Each formulation solubilized 1% (w/w) of pomegranate peel extract and was evaluated regarding in vitro release behavior, skin permeation/retention, antioxidant activity, and in vitro sun protection factor (SPF). All investigated MEs provided sustained release of punicalagin (≈10–17% of the applied dose in 8 h). ME-A, based on an alkyl polyglucoside surfactant, showed a significantly higher cumulative release of punicalagin (60.4 µg/cm2) compared with ME-E and ME-P. In skin penetration/permeation studies, ME-A also exhibited the highest numerical total delivery of punicalagin (≈48.2 µg/cm2 after 24 h), although differences among formulations were not statistically significant. All formulations demonstrated high antioxidant activity in the DPPH assay and measurable in vitro photoprotective potential, with SPF values ranging from approximately 11 to 14. Overall, pomegranate peel extract-loaded MEs showed potential as dermal delivery systems capable of improving solubilization and modulating skin delivery of punicalagin. The combination of agro-waste-derived bioactives with biocompatible surfactants highlights the potential of these systems as sustainable approaches for skincare formulations.

Background/Objectives: Antimicrobial resistance (AMR) is a major public health problem driven partly by inappropriate antibiotic use. Students of health studies represent future healthcare professionals with an important role in patient education, infection prevention, and antimicrobial stewardship. This study assessed knowledge, attitudes, and behaviours regarding antibiotic use and AMR among students of the Faculty of Health Studies, University of Mostar. Methods: An anonymous cross-sectional online survey was conducted in March 2025 using a self-selected convenience sample. The questionnaire was adapted from a previously published survey among Cypriot university students and distributed through student WhatsApp groups and by e-mail. Of 1113 invited students, 220 completed the survey, yielding a response rate of 19.8%. Results: During the previous 12 months, 39.5% of respondents reported antibiotic use. Most respondents reported adherence to medical instructions regarding dosage and duration of therapy, while 20.5% reported self-medication with antibiotics and 29.5% reported keeping unused antibiotics at home. Approximately 42% perceived antibiotics as easy or very easy to obtain without a prescription. Only 36.4% of respondents correctly distinguished antibiotics from other medications. Although most respondents recognised that bacteria can develop resistance, misconceptions persisted regarding humans and viruses. Differences between study programmes were observed for some attitudes and perceptions, whereas gender and year of study were not significantly associated with most responses. Conclusions: Health studies students demonstrated partial knowledge of antibiotics and AMR, together with behaviours that may contribute to inappropriate antibiotic use. Strengthened curricular content on rational antibiotic use, infection management, infection prevention, and antimicrobial stewardship appears justified. The findings are also consistent with the need to consider broader stewardship measures, including better enforcement of existing prescription-only dispensing requirements in Bosnia and Herzegovina.

Oral anticoagulation (OAC) and antiplatelet therapy (APT) represent a well-established preventative strategy against stroke, stent-related, and coronary ischemic events in patients with atrial fibrillation (AF) and coronary artery disease (CAD) following percutaneous coronary intervention (PCI). Less is known about the efficacy and safety of OAC as monotherapy compared with combined antithrombotic therapy in the subgroup of patients with drug-eluting stent (DES) implantation. To investigate whether deescalating from combination therapy of OAC with single APT to OAC monotherapy provides similar protection from major ischemic and bleeding endpoints in patients with AF and stable CAD following DES implantation. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) that compared OAC monotherapy (vitamin K antagonist or direct oral anticoagulant) with combination antithrombotic therapy of OAC plus single APT in patients with AF and CAD who underwent PCI with DES and reported the efficacy and safety composite outcomes of mortality, ischemia (myocardial infarction, stroke, or systemic embolism), and major bleeding or clinically relevant bleeding (CRNB). Cochrane's Review Manager Version 7.12.0 (RevMan, 2024) was used for statistical analysis to estimate pooled effects of hazard ratio (HR) with 95% confidence intervals (CI) under a random-effects model. Heterogeneity was examined with I² statistics. We included four RCTs comprising a total of 2570 patients, of whom 1302 (51%) were treated with OAC monotherapy, and the remaining 1268 (49%) were treated with combination therapy of OAC+APT. Median follow-up ranged from 12 to 30 months. There was no statistically significant difference in the efficacy endpoints of major ischemic composite (HR 0.94; 95% CI 0.65 to 1.36; p=0.75; Figure 1A) and the net clinical composite (HR 0.77; 95% CI 0.37 to 1.60; p=0.49; Figure 1B) between OAC monotherapy and OAC+APT combination therapy. However, there was a statistically significant reduction in the safety endpoint composite of major bleeding or CRNB with OAC monotherapy (HR 0.47; 95% CI 0.30 to 0.75; p=0.001; Figure 2A) compared with OAC+APT combination therapy, which was consistent in a sensitivity analysis of patients treated with predominantly new-generation DES (HR 0.38; 95% CI 0.25 to 0.59; p<0.0001; Figure 2B). Among patients with AF and prior PCI with DES implantation, OAC monotherapy statistically significantly reduced major bleeding or CRNB endpoint by 52% compared with combined antithrombotic therapy, but there was no significant difference between groups in terms of major ischemia or net clinical benefit.OAC Figure 1For image description, please refer to the figure legend and surrounding text.  OAC Figure 2For image description, please refer to the figure legend and surrounding text.

Inclisiran effectively reduces low-density lipoprotein cholesterol (LDL-C) by suppressing proprotein convertase subtilisin/kexin type 9 (PSCK9) in patients on maximally tolerated statins with atherosclerotic cardiovascular disease (ASCVD) or risk equivalent. However, less is known about the efficacy of inclisiran as a monotherapy strategy for LDL-C reduction in patients with elevated levels but who are not on statins, ezetimibe, or any other lipid-lowering therapy (LLT). To investigate whether the lipid-lowering efficacy of inclisiran in LDL-C reduction indicates a significant pharmacodynamic effect regardless of baseline cardiovascular risk in patients with hypercholesterolemia without any LLT. We conducted a comprehensive search of PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing inclisiran sodium at dose of 300 mg (equivalent to 284 mg inclisiran) with placebo in adults with hypercholesterolemia who were not on statin, ezetimibe, nor any other LLT at baseline for evaluating the lipid-lowering efficacy of inclisiran as monotherapy. Outcomes of interest were (1) primary efficacy endpoint as percentage change in LDL-C from baseline, in patients without any background LLT and in those without statin use, and (2) percentage change in PCSK9 levels from baseline. R software version 4.3.1 was used for statistical analysis to estimate pooled effects of mean difference (MD) and 95% confidence intervals (CI) under e random-effects model. Heterogeneity was examined with I² statistics. We included five RCTs comprising 540 patients, of whom 311 (58%) were treated with inclisiran monotherapy, and the remaining 229 (42%) received placebo. Median follow-up ranged from 6 to 18 months (or 183 to 540 days). When compared with placebo, patients treated with inclisiran monotherapy who were not on any LLT had a significant decrease in percentage change in LDL-C from baseline (MD −46.24%; 95% CI −51.35 to −41.12; p<0.01; Figure 1A), with no significant difference when stratified by low risk versus high-risk population (test for subgroup difference p=0.33; Figure 1A). Similarly, inclisiran monotherapy lowered the LDL-C from baseline in patients without statin at baseline by about 53% more compared with placebo (MD −52.57%; 95% CI −62.34 to −42.80; p<0.01; Figure 1B). Moreover, the inclisiran group showed a significant 77% reduction in PCSK9 levels compared with the placebo group (MD −77.29%; 95% CI −84.31 to −70.27; p<0.01; Figure 2A). In this meta-analysis of RCTs evaluating patients with hypercholesterolemia without any background LLTs, inclisiran monotherapy significantly reduced percentage change in LDL-C from baseline, regardless of ASCVD risk. These findings were consistent in a sensitivity analysis only in patients without statin use at baseline, as well as in reduction of PSCK9 levels.Inclisiran Figure 1For image description, please refer to the figure legend and surrounding text.  Inclisiran Figure 2For image description, please refer to the figure legend and surrounding text.

In patients with heart failure with reduced ejection fraction (HFrEF), the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan has consistently demonstrated a beneficial therapeutic effect, vastly in non-Chagas trials. Less is known about the efficacy and safety of sacubitril-valsartan compared with standard of care in patients with Chagas cardiomyopathy, a common but often neglected etiology of nonischemic HFrEF. We aimed to perform a systematic review and meta-analysis to investigate whether sacubitril-valsartan is superior to enalapril in patients with heart failure (HF) due to Chagas cardiomyopathy. PubMed, Embase and Cochrane database were searched for randomized controlled trials (RCTs) that compared sacubitril-valsartan with enalapril in patients with HF due to Chagas cardiomyopathy. Efficacy outcomes were (1) cardiovascular (CV) death; (2) HF hospitalization; (3) relative change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline; and safety outcomes were (4) serious adverse events (SAEs); and (5) drug discontinuation due to adverse events (AEs). Cochrane's Review Manager Version 7.2.0 (RevMan, 2024) was used for all statistical analyses. Heterogeneity was examined with I² statistics. Hazard ratios (HR), risk ratios (RR), and mean differences (MD) with 95% confidence intervals (CIs) were pooled using an inverse-variance random-effects model. Three RCTs comprising 1,112 patients were included, of whom 463 (38%) were females. A total of 615 (50.02%) patients received sacubitril–valsartan, while 610 (49.8%) were treated with enalapril. The mean age was 63.67±10.6 years, and the mean left ventricular ejection fraction (LVEF) was 29.8%±7.2%. There was no statistically significant difference in CV death (HR 0.92; 95% CI 0.72 to 1.18; p=0.51; I²=0; Figure 1A) and HF hospitalization (HR 0.93; 95% CI 0.72 to 1.20; p=0.59; I²=0; Figure 1B) between sacubitril-valsartan and enalapril groups. However, there was a statistically significant reduction in NT-proBNP favoring enalapril over sacubitril-valsartan (MD 0.68; 95% CI 0.63 to 0.73; p<0.00001; I²=0; Figure 1C). No statistically significant difference in SAEs was found between the two treatment arms (RR 0.90; 95% CI 0.79 to 1.03; p=0.12; I²=0; Figure 2A), but there was a trend towards fewer drug discontinuations due to AEs with sacubitril–valsartan compared with enalapril (RR 0.51; 95% CI 0.26 to 1.01; p=0.05; I²=32% Figure 2B). In this meta-analysis of 1,112 patients with HF due to Chagas cardiomyopathy, sacubitril-valsartan did not statistically significantly reduce CV death or HF hospitalization, relative to enalapril. There was a significant difference between groups in terms of NT-proBNP reduction favoring enalapril. Moreover, sacubitril-valsartan was not superior to enalapril with respect to safety outcomes.Figure 1.Efficacy outcomes.For image description, please refer to the figure legend and surrounding text.Figure 2.Safety outcomes.For image description, please refer to the figure legend and surrounding text.