Associations between Life's Essential 8 and depression among US adults.

Few studies have examined the association of Life's Essential 8 (LE8) with depression among US adults. This is a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2020. LE8 score was measured as the mean score of eight metrics (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipid, blood glucose, and blood pressure). CVH was categorized into low, moderate, and high according to tertiles of LE8 score. Depression was defined based on the 9-Item Patient Health Questionnaire (PHQ-9). Weighted logistic regressions were conducted to assess the associations of depression with CVH. Compared with participants with low CVH, the fully adjusted ORs of depression were 0.45 (0.37, 0.55) in the moderate CVH and 0.21 (0.15, 0.30) in the high CVH participants, respectively. The results remained robust in subgroup and sensitivity analyses. All eight LE8 metrics were negatively associated with depression, while nicotine exposure and sleep health were identified as two major metrics contributing to the association. Better CVH evaluated by LE8 was associated with decreased depression prevalence among US adults. Adherence to a higher CVH score, especially targeting smoking cessation and proper sleep duration, might be beneficial for prevention of depression.

Risk Factors for In-Hospital Seizures of Aneurysmal Subarachnoid Hemorrhage After Endovascular Treatment: A Real-World Study.

BACKGROUND AND PURPOSE: The occurrence of in-hospital seizures for aneurysmal subarachnoid hemorrhage (aSAH) ranges from 3.7% to 15.2%, and seizures remain an important factor affecting patient prognosis. Therefore, the timely identification of patients at a higher risk for aSAH-associated seizures after endovascular treatment is of paramount importance. This study aims to analyze the risk factors for in-hospital seizures after endovascular treatment for aSAH. METHODS: The study comprised 547 patients at 3 centers from January 2019 to September 2021. In the context of this study, 2 models were utilized: the first model involved no variable adjustment, while the second model included all potential confounders in the multivariate logistic regression analysis. Additionally, the dose-response relationship between biomarkers and seizure occurrence was assessed using restricted cubic spline. RESULTS: Among these patients, 28 (5.1%) developed seizures during hospitalization. In Model 2, the modified Fisher score (adjusted odds ratio [OR]: 3.138, 95% confidence interval [CI]: 1.226-8.036), body mass index (adjusted OR: 0.852, 95% CI: 0.749-0.970), aspect ratio (adjusted OR: 0.264, 95% CI: 0.115-0.604), and aspartate transaminase (adjusted OR: 1.017, 95% CI: 1.001-1.035) were showed as factors contributing to an increased risk of aSAH-associated seizures. CONCLUSIONS: Body mass index, aspartate transaminase, aspect ratio, modified Fisher scores, and Hunt-Hess scores were correlated with the formation of aSAH-associated seizures after endovascular treatment.

New pimarane diterpenoids with antibacterial activity from fungus Arthrinium sp. ZS03.

A comprehensive chemical study of the endophytic fungus Arthrinium sp. ZS03, associated with Acorus tatarinowii Schott, yielded eleven pimarane diterpenoids (compounds 1-11), including seven novel compounds designated arthrinoids A-G (1-7). The determination of their structures and absolute configurations was achieved through extensive spectroscopic techniques, quantum chemical calculations of electronic circular dichroism (ECD), and single-crystal X-ray diffraction analysis. Furthermore, 7 demonstrated inhibitory activity against Klebsiella pneumoniae, comparable to the reference antibiotic amikacin, with a minimum inhibitory concentration (MIC) of 8 µg·mL-1.

High glucose promotes atherosclerosis by regulating miRNA let7d-5p level.

BACKGROUND: MiRNA let7d-5p has been recently reported to be abnormally expressed in diabetes-associated atherosclerosis (AS). However, it still remains unknown how let7d-5p contributes to the process of atherosclerosis. METHODS: Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d-5p was assessed using quantitative RT-PCR (qRT-PCR). A series of in vitro experiments was used to determine the roles of let7d-5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). RESULTS: We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d-5p. In VSMCs, the expression of miRNA let7d-5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d-5p, whereas the opposite was true when let7d-5p was inhibited, according to gain and loss of function studies. Mechanically, let7d-5p might activate the GSK3ß/ß-catenin signaling pathway via binding to the high mobility group AT-Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP-1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d-5p levels. CONCLUSIONS: High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d-5p/HMGA2/GSK3ß/ß-catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d-5p.

Interference-induced generation of a chirp-free short isolated attosecond pulse in the water window region with multicolor laser fields.

Compensating for the intrinsic attosecond chirp (atto-chirp) of wideband high-order harmonics in the water window region is a significant challenge, in order to obtain isolated attosecond pulses (IAPs) with a width of tens of attoseconds (as). Here, we propose to realize the generation of IAP with duration as short as 20 as, central energy of 365 eV, and bandwidth exceeding 150 eV from chirp-free high harmonics generated by a four-color driving laser, without the necessity for atto-chirp compensation with natural materials. Unlike any other gating methods that an IAP arises from only one electron ionization event, we take advantage of the interference between harmonic radiation produced by multiple ionizing events. We further demonstrate that such chirp-free short IAP survives after taking account of macroscopic propagation effects. Given that the synthesized multicolor laser field can also effectively increase the harmonic flux, this work provides a practical way for experiments to generate the broad bandwidth chirp-free IAPs in the water window region.

Unveiling Coherent Control of Halomethane Dissociation Induced by a Single Strong Ultraviolet Pulse.

We present a theoretical investigation into the coherent control of photodissociation reactions in halomethanes, specifically focusing on CH2BrCl by manipulating the spectral phase of a single femtosecond laser pulse. We examine the photodissociation of CH2BrCl under an ultrashort pulse with a quadratic spectral phase and reveal the sensitivity of both the total dissociation probability and the resulting radical products (Br+CH2Cl and Cl+CH2Br) to chirp rates. To gain insights into the underlying mechanism, we calculate the population distributions of excited vibrational states in the ground electronic state, demonstrating the occurrence of resonance Raman scattering (RRS) in the strong-field limit regime. By utilizing chirped pulses, we show that this RRS phenomenon can be suppressed and even eliminated through quantum destructive interference. This highlights the high sensitivity of photodissociation into Cl+CH2Br to the spectral phase, showcasing a phenomenon that goes beyond the traditional one-photon photodissociation of isolated molecules in the weak-field limit regime. These findings emphasize the importance of coherent control in the exploration and utilization of photodissociation in polyatomic molecules, paving the way for new advancements in chemical physics and femtochemistry.

Blood inflammatory biomarkers predict in-hospital pneumonia after endovascular treatment of aneurysm in patients with aneurysmal subarachoid hemorrhage.

The systemic inflammatory response index (SIRI) is a well-known marker of systemic inflammation reflecting the body's inflammatory/immune state. The study aimed to evaluate the relationship between the SIRI on admission and aneurysmal subarachnoid hemorrhage (aSAH)-associated pneumonia and compare with other currently used bio-markers. We reviewed 562 successive patients with aneurysmal SAH who underwent endovascular treatment between January 2019 and September 2021. ASAH-associated pneumonia was diagnosed using the modified Centers for Disease Control and Prevention criteria. The SIRI on admission was calculated as monocyte count × neutrophil count / lymphocyte count. Multiple logistic regression models were used for data analysis. A total of 158 (28.11%) patients developed aSAH-associated pneumonia. Using the Multiple logistic regression analysis, a notable dose-response association was found between the elevated SIRI (fourth quartile) and aSAH-associated pneumonia (adjusted odds ratio = 6.759; 95% confidence interval [CI], 3.280-13.930; p < 0.001 [p for trend < 0.001]). The SIRI (0.701, 95% CI: 0.653-0.749) presented a higher area under the curve (AUC) than systemic immune- inflammation index (SII) (0.669, 95% CI: 0.620-0.718) (p = 0.089); neutrophil-to-lymphocyte ratio (NLR) (0.665, 95% CI: 0.616-0.714) (p = 0.035) and platelet-lymphocyte ratio (PLR) (0.587, 95% CI: 0.534-0.641) (p < 0.001). A higher SIRI on admission was associated with aSAH-associated pneumonia, which may guide further clinical trials of prophylactic antibiotic therapy.

Combined exposure to multiple metals on hypertension in NHANES under four statistical models.

Metals exposure has gained increasing attention in the hypertension prevention. However, previous studies have focused on the impacts of single or separated metals on hypertension, and the critical metals contributing to the prevalence of hypertension are still under discussion. We collected data from 5092 participants across three consecutive National Health and Nutrition Examination Survey (NHANES) circles (2011-2016). Weighted logistic regression, weighted quantile sum (WQS) regression, quantile-based g-computation (QGC), and Bayesian kernel machine regression (BKMR) analyses were conducted to evaluate the combined and individual effects of 15 urinary metals, as well as to identify the critical metals on the development of hypertension. In our study, the weighted prevalence of hypertension was 37.9%, and the average age was 47.42 years. Manganese, uranium and tin were found as the independent risk factors for hypertension, while barium, lead, and thallium were found to have protective effects against hypertension. Lead, barium, tungsten, uranium, and tin were determined as critical elements for the prediction of hypertension. No significant interaction relationship was detected between multiple metals. There might be potential positive combined effects of urinary metal mixture on hypertension. Tungsten, uranium, and tin were positively associated with hypertension while lead and barium were negatively associated with hypertension. The underlying mechanisms of urinary metal exposure on the risk of hypertension deserve further investigations.

Association between higher systemic immune inflammation index (SII) and deep vein thrombosis (DVT) in patients with aneurysmal subarachnoid hemorrhage (aSAH) after endovascular treatment.

Inflammation contributes to deep vein thrombosis (DVT) formation in patients with aSAH after endovascular treatment. The relationship between systemic immune-inflammatory index (SII) as an inflammatory marker and DVT formation remains unclear. Thus, this study aims to evaluate the association between SII and aSAH-associated DVT following endovascular treatment. We enrolled 562 consecutive patients with aSAH after endovascular treatment at three centers from January 2019 to September 2021. The endovascular treatments included simple coil embolization and stent-assisted coil embolization. Deep venous thrombosis (DVT) was assessed by Color Doppler ultrasonography (CDUS). Multivariate logistic regression analysis was used to establish the model. We assessed the association of the SII, neutrophil-to-lymphocyte ratio (NLR), the systemic inflammatory response index (SIRI), platelet-lymphocyte ratio (PLR), and DVT by using restricted cubic spline (RCS). ASAH-associated DVT was found in 136 (24.20%) patients. Based on the multiple logistic regression analysis, the correlation was found between aSAH-associated DVT and elevated SII (fourth quartile) (adjusted odds ratio = 8.20 [95% confidence interval, 3.76-17.92]; p < 0.001 [p for trend < 0.001]), elevated NLR (fourth quartile) (adjusted odds ratio = 6.94 [95% confidence interval, 3.24-14.89]; p < 0.001 [p for trend < 0.001]), elevated SIRI (fourth quartile) (adjusted odds ratio = 4.82 [95% confidence interval, 2.36-9.84]; p < 0.001 [p for trend < 0.001]), and elevated PLR (fourth quartile) (adjusted odds ratio = 5.49 [95% confidence interval, 2.61-11.57]; p < 0.001 [p for trend < 0.001]). The increased SII was correlated with the formation of aSAH-associated DVT after endovascular treatment.

Role of BMI in the relationship between dietary inflammatory index and non-alcoholic fatty liver disease: an intermediary analysis.

OBJECTIVE: Previous studies have indicated that a pro-inflammatory diet is associated with non-alcoholic fatty liver disease (NAFLD), but the role of BMI remains ambiguous. We aim to study the intermediary effect of BMI on the relationship between dietary inflammatory properties and NAFLD. METHODS: A total of 19536 adult participants from the National Health and Nutrition Examination Surveys (NHANES) were included. Dietary inflammatory index (DII) was used to evaluate the dietary inflammatory properties and NAFLD was diagnosed by non-invasive biomarkers. Weighted multivariable logistic regression models estimated ORs and 95% CIs between DII and incidence of NAFLD. Interaction effect between DII and BMI on NAFLD was tested and the mediation analysis of BMI was performed. RESULTS: Higher DII scores, representing higher inflammatory potential of diet, were positively associated with a higher risk of NAFLD. Compared with the first quartile of DII, people from the second quartile (OR: 1.23 [95% CI: 1.04, 1.46]) to the fourth quartile (OR: 1.59 [95% CI: 1.31, 1.94]) have a higher risk of NAFLD before adjustment for BMI. The overall association was completely mediated by BMI (89.19%). CONCLUSIONS: Our findings suggested that a higher pro-inflammatory potential diet was associated with a higher prevalence of NAFLD, and this association might be mediated by BMI.

Association of elevated neutrophil-to-lymphocyte ratio with increased intracranial aneurysm stability scores and aneurysm growth.

BACKGROUND AND PURPOSE: Inflammation involves in the progression of intracranial aneurysms (IAs). However, whether the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory marker links to IAs stability is unidentified. This study was performed to assess the association of the NLR with IAs stability. METHODS: We retrospectively reviewed the medical records of patients diagnosed with unruptured IAs from January 2014 to June 2018. According to the quartiles of the NLR, patients with unruptured IAs were categorized into four groups. We evaluated the association between the NLR and IAs stability scores and IAs growth. Multiple logistic regression models were used in the analysis. RESULTS: A significant dose-response association was found between the NLR with IAs stability scores and IAs growth. After adjustment for potential confounders, an elevated NLR (fourth quartile) was associated with increased PHASES score (>5) (adjusted odds ratio [OR], 2.007; 95% confidence interval [CI], 1.361-2.960; p<0.001 [p for trend <0.001]), increased ELAPSS score (>15) (adjusted OR, 1.581; 95% CI, 1.074-2.328; p=0.020 [p for trend =0.001]), increased JAPAN 3-year rupture risk score (>5) (adjusted OR, 1.512; 95% CI, 1.033-2.215; p=0.034 [p for trend <0.001]), and IAs growth (adjusted OR, 16.759; 95% CI, 3.022-92.928; p=0.001 [p for trend <0.001]). CONCLUSION: An elevated NLR was associated with increased IAs stability scores and IAs growth. The association between NLR and IAs stability need further investigate.

Orbital-resolved photoelectron momentum distributions of F- ions in a counter-rotating bicircular field.

We present a theoretical study of the orbital-resolved photoelectron momentum distributions (PMDs) of F- ions by a two-color counter-rotating circularly polarized field. We show that the PMDs of F- ions can be modulated from an isotropic symmetric distribution into a three-lobe one by adding a weak fundamental counter-rotating field to the intense second harmonic circularly polarized field, and this modulation strongly depends on the initial atomic orbital. The PMDs simulated by the strong-field approximation method show good agreement with those obtained by solving the time-dependent Schrödinger equation. Based on the strong-field approximation method, we find that the radial momentum shift of PMDs for different orbitals is the fingerprint of orbital-dependent initial momentum at the tunnel exit. More importantly, we demonstrate that the lobes in PMDs appear in sequential order, highlighting that the scheme can be viewed as controllable rotating temporal Young's two-slit interferometer.

Controllable waveform terahertz generation using rippled plasma driven by an inhomogeneous electrostatic field.

We theoretically present the waveform controls of terahertz (THz) radiations generated from homogeneous and rippled plasma within inhomogeneous external electrostatic field. The Particle-in-cell (PIC) simulations is implemented to demonstrate generation and controllability of three types of THz pulses: single frequency THz pulse in homogeneous plasma, broadband THz pulse and dual frequency THz pulse in rippled plasma. The single frequency THz pulse can be tuned via shifting the knob of electron density of homogeneous plasma. Waveform of broadband THz pulse can be regulated into an envelope-like shape by varying amplitude of electron density of rippled plasma. The two center frequencies' interval of dual frequency THz pulse can be controlled by wave numbers of density distribution of rippled plasma. This work provides a potential means to generate the dual frequency THz pulses with two harmonic frequencies (ω+Ωω, Ω=2) or incommensurate frequencies (ω+Ωω, Ω=1.7,1.8, 2.2…).

Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y2 receptor triple agonist.

The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.

Economic evaluation of intravenous alteplase for stroke with the time of onset between 4.5 and 9 hours.

BACKGROUND: A clinical trial proved the clinical effectiveness of perfusion imaging-guided intravenous thrombolysis with alteplase for patients with acute ischemic stroke (AIS) with the time of onset between 4.5 and 9 hours. This study aimed to assess the lifetime cost-effectiveness of alteplase versus placebo from the perspective of Chinese and United States (US) healthcare payers. METHODS: A decision-analytic model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) associated with alteplase or placebo. Model inputs were extracted from published sources. Incremental costs, incremental QALYs, and incremental cost-effectiveness ratio (ICER) were calculated to evaluate the base-case scenario. One-way and probabilistic sensitivity analysis were performed to evaluate uncertainty in the results. RESULTS: In China, alteplase yielded an additional lifetime QALY of 0.126 with an additional cost of Chinese Yuan (¥) ¥9552 compared with placebo, and the ICER was ¥83 950 (US$12 157)/QALY. In the US, alteplase had a higher QALY (difference: 0.193) with a lower cost (difference: US$-2024) compared with placebo. In probabilistic sensitivity analyses, alteplase had a 42.54% to 78.3% probability of being cost-effective compared with placebo in China when the willingness-to-pay (WTP) threshold ranged from ¥72 447/QALY to ¥217 341/QALY. In the US, alteplase had a 93.47% to 93.57% probability of being cost-effective under the WTP threshold of US$100 000/QALY to US$150 000/QALY. These findings remained robust under one-way sensitivity analysis. CONCLUSION: For patients with AIS with a time of onset between 4.5 and 9 hours, perfusion imaging-guided intravenous alteplase was likely to be cost-effective in China and was cost-effective in the US when compared with placebo.

Cost-effectiveness of recombinant tissue-type plasminogen activator for acute ischaemic stroke with unknown time of onset: a Markov modelling analysis from the Chinese and US perspectives.

OBJECTIVE: The effectiveness of MRI-guided intravenous recombinant tissue-type plasminogen activator (r-tPA) for acute ischaemic stroke (AIS) with an unknown time of onset has been demonstrated by the WAKE-UP Trial. We aim to evaluate its long-term cost-effectiveness from the perspective of Chinese and US healthcare payers. METHODS: A combination of decision tree and Markov model was built to project lifetime costs and quality-adjusted life-years (QALYs) associated with intravenous r-tPA or placebo treatment. Model inputs including the transition probabilities, costs and utilities were derived from the WAKE-UP Trial, similar cost-effectiveness studies and other published sources. To compare intravenous r-tPA to placebo, we calculated incremental costs, incremental QALYs and incremental cost-effectiveness ratio (ICER). One-way sensitivity, probabilistic sensitivity and subgroup analyses were performed to evaluate uncertainty in the results. RESULTS: In China, intravenous r-tPA gained an additional lifetime QALY of 0.293 with an additional cost of the Chinese Yuan (¥) of 7871 when compared with placebo, resulting in an ICER of ¥26 870 (US$3894)/QALY. In the USA, intravenous r-tPA yielded a higher QALY (difference: 0.430) and lower cost (difference: ¥-4563) when compared with placebo. In probabilistic sensitivity analyses, intravenous r-tPA had a 97.8% and 99.8% probability of being cost-effective or cost-saving in China and the USA, respectively. These findings remained robust under one-way sensitivity and subgroup analysis except for patients with a National Institute of Health Stroke Scale Score of less than 4, between 11 and 16, and over 16. CONCLUSIONS: MRI-guided intravenous r-tPA for patients with AIS with an unknown time of onset is cost-effective in China and cost-saving in the USA.

Economic Evaluation of Ticagrelor Plus Aspirin Versus Aspirin Alone for Acute Ischemic Stroke and Transient Ischemic Attack.

Background: Although ticagrelor plus aspirin is more effective than aspirin alone in preventing the 30-day risk of a composite of stroke or death in patients with an acute mild-to-moderate ischemic stroke (IS) or transient ischemic attack (TIA), the cost-effectiveness of this combination therapy remains unknown. This study aims to determine the cost-effectiveness of ticagrelor plus aspirin compared with aspirin alone. Methods: A combination of decision tree and Markov model was built to estimate the expected costs and quality-adjusted life-years (QALYs) associated with ticagrelor plus aspirin and aspirin alone in the treatment of patients with an acute mild-to-moderate IS or TIA. Model inputs were extracted from published sources. One-way sensitivity, probabilistic sensitivity, and subgroup analyses were performed to test the robustness of the findings. Results: Compared with aspirin alone, ticagrelor plus aspirin gained an additional lifetime QALY of 0.018 at an additional cost of the Chinese Yuan Renminbi (¥) of 269, yielding an incremental cost-effectiveness ratio of ¥15,006 (US$2,207)/QALY. Probabilistic sensitivity analysis showed that ticagrelor plus aspirin had a probability of 99.99% being highly cost-effective versus aspirin alone at the current willingness-to-pay threshold of ¥72,447 (US$10,500)/QALY in China. These findings remain robust under one-way sensitivity and subgroup analyses. Conclusions: The results indicated that early treatment with a 30-days ticagrelor plus aspirin for an acute mild-to-moderate IS or TIA is highly cost-effective in a Chinese setting.

Cost-effective analysis of mechanical thrombectomy alone in the treatment of acute ischaemic stroke: a Markov modelling study.

OBJECTIVE: Recently, a randomised controlled trial (DIRECT-MT) demonstrated that mechanical thrombectomy (MT) was non-inferior to MT with intravenous alteplase as to the functional outcomes. This study aims to investigate whether MT alone is cost-effective compared with MT with alteplase in China. METHODS: A Markov decision analytic model was built from the Chinese healthcare perspective using a lifetime horizon. Probabilities, costs and outcomes data were obtained from the DIRECT-MT trial and other most recent/comprehensive literature. Base case calculation was conducted to compare the costs and effectiveness between MT alone and MT with alteplase. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the results. RESULTS: MT alone had a lower cost and higher effectiveness compared with MT with alteplase. The probabilistic sensitivity analysis demonstrated that, over a lifetime horizon, MT alone had a 99.5% probability of being cost-effective under the willingness-to-pay threshold of 1× gross domestic product per capita in China based on data obtained from the DIRECT-MT trial. These results remained robust under one-way sensitivity analysis. CONCLUSIONS: MT alone was cost-effective compared with MT with alteplase in China. However, cautions are needed to extend this conclusion to regions outside of China.

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. EXPERIMENTAL APPROACH: The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. KEY RESULTS: xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK2 tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15. CONCLUSIONS AND IMPLICATIONS: These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Inflammation index SIRI is associated with increased all-cause and cardiovascular mortality among patients with hypertension.

Background: Inflammation plays an essential role in the pathogenesis of hypertension. A novel inflammatory biomarker systemic inflammatory response index (SIRI) is related with all-cause and cardiovascular (CVD) mortality, while the role of SIRI in hypertension patients is unclear. Methods: A total of 21,506 participants with hypertension were recruited in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. SIRI was calculated as the neutrophil count * monocyte count/lymphocyte count. Hypertension was defined according to the examination of blood pressure, prescription, and self-reported physician diagnosis. Survival status was followed through 31 December 2019. The non-linear relationship was assessed using restricted cubic spline analysis. The association of all-cause mortality with SIRI was evaluated using the Kaplan-Meier curve and the weighted Cox regression analysis. The predictive abilities were assessed with Receiver operating curve. Results: During 189,063 person-years of follow-up, 5,680 (26.41%) death events were documented, including 1,967 (9.15%) CVD related deaths. A J-shaped association was observed between SIRI and all-cause and CVD mortality. The Kaplan-Meier curve indicated the all-cause and CVD mortality risks were higher in high SIRI quartiles compared with lower SIRI quartiles. After adjusting for all covariates, the SIRI was positively associated with the all-mortality risk with HR = 1.19 (1.15, 1.22), and CVD mortality with HR = 1.19 (1.15, 1.24). The result was robust in subgroup analysis and sensitivity analysis. Conclusion: Elevated SIRI level is associated with increased all-cause and CVD mortality among patients with hypertension. SIRI is considered as a potential inflammatory biomarker in the clinical practice. Further large-scale cohort studies are required to confirm our findings.