ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1.

BACKGROUND: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis. METHODS: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques. RESULTS: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site. CONCLUSIONS: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.

A long-wavelength mitochondria-targeted fluorescent probe for imaging of peroxynitrite during dexamethasone treatment.

Peroxynitrite (ONOO-), as a strong oxidizing reactive nitrogen substance (RNS), is generated endogenously by cells. Its visualization research is crucial to understand relevant disease processes. Herein, we reported a long-wavelength mitochondria-targeted fluorescence "turn on" probe TL. The probe TL could react with ONOO- by using 4-(Bromomethyl)benzeneboronic as a reactive site, which exhibited outstanding characteristics for detection of ONOO-, thus improving response time (about 50 s), sensitivity (DL, 10.1 nM), and emission wavelength (667 nm). Besides, TL displayed well mitochondria targeting and biological visualizing of exogenous and endogenous ONOO- in biological systems. Finally, TL was used to monitor high concentration of dexamethasone-induced an up-regulation of ONOO-. This indicated that TL has excellent potential to study the fluctuation of ONOO- in the physiological and pathological system.

Characteristics of Ag-incorporated bioactive glasses prepared by a modified sol-gel method with a shortened synthesis time and without the use of catalysts.

This work presents the preparation of bioactive glasses 70SiO2-(26 - x)CaO-4P2O5-xAg2O (with x = 0, 1, 3, 10 mol%) by a modified sol-gel method with reduced synthesis time based on hydrothermal reaction in a medium without acid or base catalysts. The synthetic materials were characterized by several physical-chemical techniques such as TG-DSC, XRD, SEM, TEM, and N2 adsorption/desorption measurement. The analysis data confirmed that the glass sample not containing Ag has a completely amorphous structure, while glass samples containing Ag exhibited a pure phase of metallic nano-silver in the glass amorphous phase. All the synthetic glasses have mesoporous structures with particle sizes of less than 30 nm. The addition of silver to the bioactive glass structure in general did not drastically reduce the specific surface areas and pore volumes of glasses as in previous studies. The bioactivity of the silver-incorporated glasses did not reduce, and even increased in the cases of bioactive glass containing 3, and 10 mol% of Ag2O. The biocompatibility of synthetic glasses with fibroblast cells (L-929) was confirmed, even with glass containing high amounts of Ag. Representatively, Ag-incorporated glass samples (sample x = 3, and x = 10) were selected to check the antibacterial ability using bacterial strain Pseudomonas aeruginosa ATCC 27853 (Pa). The obtained results indicated that these glasses exhibited good antibacterial ability to Pseudomonas aeruginosa. Thus, the synthetic method in this study proved to be a fast, environmentally friendly technique for synthesizing Ag-incorporated glass systems. The synthesized glasses show good bioactive, biocompatible, and antibacterial properties.

Glucose-lowering treatment patterns in patients with diabetic kidney disease.

OBJECTIVES: Recent trials of glucose-lowering drugs (GLDs) have drawn attention to renal outcomes. Our goal was to understand how patients with diabetic kidney disease (DKD) are treated in general practices in the United States. STUDY DESIGN: Retrospective cohort study using a national-level claims data set and electronic health records. METHODS: Patients (≥ 18 years) with type 2 diabetes, whose estimated glomerular filtration rates (eGFRs) were between 15 and 89 mL/min/1.73 m2 between 2016 and 2018, were selected. Use of different GLDs during a 12-month period was examined across all eGFR levels. RESULTS: Of the 25,486 sample patients, 69.2%, 18.9%, 9.6%, and 2.3% had an eGFR in the ranges of 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m2, respectively. Metformin was used by nearly 33% of patients with an eGFR of 30 to 44 mL/min/1.73 m2 and by 10% of patients with an eGFR less than 30 mL/min/1.73 m2. Less than 10% (across all eGFR levels) of patients used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Use of insulin was more frequent among patients with a lower eGFR (P < .05). The findings were similar in subgroups with different hemoglobin A1c levels (< 7% and ≥ 7%). CONCLUSIONS: Real-world treatment of DKD in the United States is suboptimal. Inappropriate use of some GLD classes, especially in advanced DKD stages, was found along with lower than expected use of modern agents that are considered safe and effective to treat glycemic outcomes. Efforts may be needed to improve understanding of safety, glycemic efficacy, and overall clinical value of GLDs across DKD stages.

Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation.

Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr-/- mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. I mp or ta ntly, p ha rm ac ol ogical sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr-/- mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.

Menin inhibition suppresses castration-resistant prostate cancer and enhances chemosensitivity.

Disease progression and therapeutic resistance of prostate cancer (PC) are linked to multiple molecular events that promote survival and plasticity. We previously showed that heat shock protein 27 (HSP27) acted as a driver of castration-resistant phenotype (CRPC) and developed an oligonucleotides antisense (ASO) against HSP27 with evidence of anti-cancer activity in men with CRPC. Here, we show that the tumor suppressor Menin (MEN1) is highly regulated by HSP27. Menin is overexpressed in high-grade PC and CRPC. High MEN1 mRNA expression is associated with decreased biochemical relapse-free and overall survival. Silencing Menin with ASO technology inhibits CRPC cell proliferation, tumor growth, and restores chemotherapeutic sensitivity. ChIP-seq analysis revealed differential DNA binding sites of Menin in various prostatic cells, suggesting a switch from tumor suppressor to oncogenic functions in CRPC. These data support the evaluation of ASO against Menin for CRPC.

Lifetime Cost-effectiveness of Oral Semaglutide Versus Dulaglutide and Liraglutide in Patients With Type 2 Diabetes Inadequately Controlled With Oral Antidiabetics.

PURPOSE: To estimate the incremental cost-utility ratio of oral semaglutide (14 mg once daily) vs other glucagon-like peptide 1 receptor agonist treatments among adults with type 2 diabetes that was inadequately controlled with 1 to 2 oral antidiabetic drugs from a US payer perspective. METHODS: A state-transition model with a competing risk approach was developed for diabetic complications and risk of cardiovascular events based on the UK Prospective Diabetes Study Outcomes Model 1 equations. Baseline population characteristics reflect the PIONEER 4 trial (Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus) of oral semaglutide. Model comparators included subcutaneous semaglutide, dulaglutide, and liraglutide. Treatment effects (change in glycosylated hemoglobin, weight, and systolic blood pressure) were estimated by network meta-analysis. Drug, management, and event costs (in 2019 US dollars), survival after nonfatal events, and utilities were obtained from the literature. Costs and quality-adjusted life-year (QALY) outcomes were discounted at 3% annually over a lifetime horizon. Probabilistic and 1-way sensitivity analyses were performed. FINDINGS: Total estimated costs and QALYs were $144,065 and 12.98 for oral semaglutide, $145,721 and 12.96 for dulaglutide, $145,833 and 12.99 for SC semaglutide, and $149,428 and 12.97 for liraglutide, respectively. Oral semaglutide was less costly and more effective than dulaglutide and liraglutide but less costly than subcutaneous semaglutide with similar effectiveness. Oral semaglutide was favored versus subcutaneous semaglutide in 52.10% of model replications at a willingness-to-pay of $150,000 per QALY. IMPLICATIONS: Oral semaglutide is predicted to offer health benefits similar to subcutaneous semaglutide and ahead of dulaglutide and liraglutide. Oral semaglutide is a cost-effective glucagon-like peptide 1 receptor agonist treatment option.

Antisense Oligonucleotide-Based Therapeutic against Menin for Triple-Negative Breast Cancer Treatment.

The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2) and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer; however, the functions of menin in TNBC remain unknown. Here, we have demonstrated that menin is expressed in various TNBC subtypes with the strongest expression in the TNBC Hs 578T cells. The depletion of menin by an antisense oligonucleotide (ASO) inhibits cell proliferation, enhances apoptosis in Hs 578T cells, highlighting the oncogenic functions of menin in this TNBC model. ASO-based menin silencing also delays the tumor progression of TNBC xenografts. Analysis of the menin interactome suggests that menin could drive TNBC tumorigenesis through the regulation of MLL/KMT2A-driven transcriptional activity, mRNA 3'-end processing and apoptosis. The study provides a rationale behind the use of ASO-based therapy, targeting menin in monotherapy or in combination with chemo or PARP inhibitors for menin-positive TNBC treatments.

Association of public health interventions and COVID-19 incidence in Vietnam, January to December 2020.

BACKGROUND: Vietnam implemented various public health interventions such as contact tracing and testing, mandatory quarantine, and lockdowns in response to coronavirus disease 2019 (COVID-19). However, the effects of these measures on the epidemic remain unclear. METHODS: This article describes the public health interventions in relation to COVID-19 incidence. Maximum likelihood estimations were used to assess containment delays (time between symptom onset and start of isolation) and multivariable regression was employed to identify associated factors between interventions and COVID-19 incidence. The effective reproductive numbers (Rt) were calculated based on transmission pairs. RESULTS: Interventions were introduced periodically in response to the epidemic. Overall, 817 (55.4%) among 1474 COVID-19 cases were imported. Based on a serial interval of 8.72 ± 5.65 days, it was estimated that Rt decreased to below 1 (lowest at 0.02, 95% CI 0-0.12) during periods of strict border control and contact tracing, and increased ahead of new clusters. The main method to detect cases shifted over time from passive notification to active case-finding at immigration or in lockdown areas, with containment delays showing significant differences between modes of case detection. CONCLUSIONS: A combination of early, strict, and consistently implemented interventions is crucial to control COVID-19. Low-middle income countries with limited capacity can contain COVID-19 successfully using non-pharmaceutical interventions.

Nucleoside-Lipid-Based Nanoparticles for Phenazine Delivery: A New Therapeutic Strategy to Disrupt Hsp27-eIF4E Interaction in Castration Resistant Prostate Cancer.

Heat shock protein 27 (Hsp27) has an established role in tumor progression and chemo-resistance of castration-resistant prostate cancer (CRPC). Hsp27 protects eukaryotic translation initiation factor 4E (eIF4E) from degradation, thereby maintaining survival during treatment. Phenazine derivative compound #14 was demonstrated to specifically disrupt Hsp27/eIF4E interaction and significantly delay castration-resistant tumor progression in prostate cancer xenografts. In the present work, various strategies of encapsulation of phenazine #14 with either DOTAU (N-[5'-(2',3'-dioleoyl)uridine]-N',N',N'-trimethylammonium tosylate) and DOU-PEG2000 (5'-PEG2000-2',3'-dioleoyluridine) nucleolipids (NLs) were developed in order to improve its solubilization, biological activity, and bioavailability. We observed that NLs-encapsulated phenazine #14-driven Hsp27-eIF4E interaction disruption increased cytotoxic effects on castration-resistant prostate cancer cell line and inhibited tumor growth in castration-resistant prostate cancer cell xenografted mice compared to phenazine #14 and NLs alone. Phenazine #14 NL encapsulation might represent an interesting nanostrategy for CRPC therapy.

Estimating and mitigating the risk of COVID-19 epidemic rebound associated with reopening of international borders in Vietnam: a modelling study.

BACKGROUND: Vietnam has emerged as one of the world's leading success stories in responding to COVID-19. After a prolonged period of little to no transmission, there was an outbreak of unknown source in July, 2020, in the Da Nang region, but the outbreak was quickly suppressed. We aimed to use epidemiological, behavioural, demographic, and policy data from the COVID-19 outbreak in Da Nang to calibrate an agent-based model of COVID-19 transmission for Vietnam, and to estimate the risk of future outbreaks associated with reopening of international borders in the country. METHODS: For this modelling study, we used comprehensive data from June 15 to Oct 15, 2020, on testing, COVID-19 cases, and quarantine breaches within an agent-based model of SARS-CoV-2 transmission to model a COVID-19 outbreak in Da Nang in July, 2020. We applied this model to quantify the risk of future outbreaks in Vietnam in the 3 months after the reopening of international borders, under different behavioural scenarios, policy responses (ie, closure of workplaces and schools), and ongoing testing. FINDINGS: We estimated that the outbreak in Da Nang between July and August, 2020, resulted in substantial community transmission, and that higher levels of symptomatic testing could have mitigated this transmission. We estimated that the outbreak peaked on Aug 2, 2020, with an estimated 1060 active infections (95% projection interval 890-1280). If the population of Vietnam remains highly compliant with mask-wearing policies, our projections indicate that the epidemic would remain under control even if a small but steady flow of imported infections escaped quarantine into the community. However, if complacency increases and testing rates are relatively low (10% of symptomatic individuals are tested), the epidemic could rebound again, resulting in an estimated 2100 infections (95% projected interval 1050-3610) in 3 months. These outcomes could be mitigated if the behaviour of the general population responds dynamically to increases in locally acquired cases that exceed specific thresholds, but only if testing of symptomatic individuals is also increased. INTERPRETATION: The successful response to COVID-19 in Vietnam could be improved even further with higher levels of symptomatic testing. If the previous approaches are used in response to new COVID-19 outbreaks, epidemic control is possible even in the presence of low levels of imported cases. FUNDING: Ministry of Science and Technology (Vietnam). TRANSLATION: For the Vietnamese translation of the abstract see Supplementary Materials section.

Real-World Effectiveness of Once-Weekly Semaglutide From a US Commercially Insured and Medicare Advantage Population.

PURPOSE: Patients managing type 2 diabetes mellitus (T2DM) often require combination therapy to meet their blood glucose control targets. With limited real-world evidence focused on the use of glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies, the objective of this study was to describe the association between semaglutide once weekly (OW) initiation and changes in hemoglobin A1c (A1c) levels. METHODS: This retrospective, descriptive cohort study used the HealthCore Integrated Research Environment (HIRE) to examine commercially insured and Medicare Advantage patients who had T2DM while taking semaglutide OW from December 1, 2017, to April 30, 2019. The first semaglutide OW prescription fill was defined as the study index date. Changes in mean A1c levels and A1c target attainment were evaluated among an intention-to-treat (ITT) population (overall group). Furthermore, a persistent population (PP) analysis on the same outcomes was performed that was limited to ITT patients who were observed to continue to use semaglutide OW at the time of the postindex A1c measurement. In addition, these outcomes were explored in patients stratified based on prior use of GLP-1RA therapy (experienced vs naive) and baseline A1c values >9% (75 mmol/mol). FINDINGS: A total of 1888 patients were identified in the overall ITT group. The mean change in the overall ITT group between preindex and postindex A1c values was -0.9% percentage points (-9.8 mmol/mol) (mean preindex A1c, 8.2% [66.1 mmol/mol]) and -1.1 percentage points (-12.0 mmol/mol) (mean preindex A1c, 8.2% [66.1 mmol/mol]) in the PP subgroup (all P < 0.001). Among the subgroup of patients with a baseline A1c value >9% (75 mmol/mol), percentage point changes in A1c were -2.2 (-24.0 mmol/mol) and -2.4 (-26.2 mmol/mol) (all P < 0.001). When accounting for prior GLP-1RA use, the GLP-1RA-naive stratum had double the mean reduction in A1c compared with the GLP-1RA-experienced stratum (-1.2 [-13.1 mmol/mol] vs -0.6 [-6.6 mmol/mol] percentage points). IMPLICATIONS: Semaglutide OW is associated with clinically and statistically significant A1C reduction and increases in reaching A1 targets using real-world data, even in GLP-1RA-experienced patients, despite more frequent use of insulin or sodium glucose transport protein 2 inhibitors in this group. Target A1c attainment significantly increased overall and within all subgroups and strata, with approximately half of all patients attaining an A1c value <7% (53 mmol/mol) and three-quarters attaining an A1c value <8% (64 mmol/mol).

Testing early warning and response systems through a full-scale exercise in Vietnam.

BACKGROUND: Simulation exercises can functionally validate World Health Organization (WHO) International Health Regulations (IHR 2005) core capacities. In 2018, the Vietnam Ministry of Health (MOH) conducted a full-scale exercise (FSX) in response to cases of severe viral pneumonia with subsequent laboratory confirmation for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to evaluate the country's early warning and response capabilities for high-risk events. METHODS: An exercise planning team designed a complex fictitious scenario beginning with one case of severe viral pneumonia presenting at the hospital level and developed all the materials required for the exercise. Actors, controllers and evaluators were trained. In August 2018, a 3-day exercise was conducted in Quang Ninh province and Hanoi city, with participation of public health partners at the community, district, province, regional and national levels. Immediate debriefings and an after-action review were conducted after all exercise activities. Participants assessed overall exercise design, conduction and usefulness. RESULTS: FSX findings demonstrated that the event-based surveillance component of the MOH surveillance system worked optimally at different administrative levels. Detection and reporting of signals at the community and health facility levels were appropriate. Triage, verification and risk assessment were successfully implemented to identify a high-risk event and trigger timely response. The FSX identified infection control, coordination with internal and external response partners and process documentation as response challenges. Participants positively evaluated the exercise training and design. CONCLUSIONS: This exercise documents the value of exercising surveillance capabilities as part of a real-time operational scenario before facing a true emergency. The timing of this exercise and choice of disease scenario was particularly fortuitous given the subsequent appearance of COVID-19. As a result of this exercise and subsequent improvements made by the MOH, the country may have been better able to deal with the emergence of SARS-CoV-2 and contain it.

Impact of Weight Change in Adults with Type 2 Diabetes Mellitus: A Literature Review and Critical Analysis.

OBJECTIVE: Weight reduction is a key component of diabetes management in adults with type 2 diabetes mellitus (T2DM), yet the benefits of weight loss in T2DM patients have been difficult to quantify. We examined the medical literature regarding the relationships between weight change and 1) glycemic control and 2) cost and resource use. METHODS: Systematic searches were conducted in the electronic databases Embase, MEDLINE, and the Cochrane Database of Systematic Reviews to identify publications regarding the impact of weight change on T2DM outcomes from 2007 onward. Identified publications were screened for relevance against predefined eligibility criteria, and methodological approaches and results were extracted. Evidence for the impact of weight change on outcomes was evaluated and used to identify strengths, limitations, and gaps in the current literature. RESULTS: The number of studies meeting eligibility criteria for each outcome was: glycemic control (n=38) and cost and resource use (n=11). The relationship between weight change and glycemic control was dependent on the interplay of multiple factors, eg, the weight loss interventions employed, the antidiabetic medication classes used, the time horizon, and baseline BMI and glycemic control. With respect to cost and resource use, the review indicated that savings were associated with weight loss, and increased costs were associated with weight gain. CONCLUSION: Studies regarding weight change in T2DM patients demonstrated varying effects on glycemic control and a positive association with costs and resource use, where weight loss was associated with decreased costs and resource use. Future studies may be able to clarify these relationships.

In-Depth Investigation of a Donor-Acceptor Interaction on the Heavy-Group-14@Group-13-Diyls in Transition-Metal Tetrylone Complexes: Structure, Bonding, and Property.

Stabilization for tetrylone complexes, which carry ylidone(0) ligands [(CO)5W-X (YCp*)2] (X = Ge, Sn, Pb; Y = B-Tl), has become an active theoretical research because of their promising application. Structure, bonding, and quantum properties of the transition-metal donor-acceptor complexes were theoretically investigated at the level of theory BP86 with several types of basis sets including SVP, TZVPP, and TZ2P+. The optimized structures reveal that all ligands X (YCp*)2 are strongly bonded in tilted modes to the metal fragment W(CO)5, and Cp* rings are mainly η5-bonded to atom X. DFT-based bonding analysis results in an implication that the stability of W-X bond strength primarily stems from the donation (CO)5W ← X(YCp*)2 formed by both σ- and π-bondings and the electrostatic interaction ΔE elstat. The W-X bond possesses a considerable polarizability toward atom X, and analysis on its hybridization is either sp2-characteristic or mainly p-characteristic. EDA-NOCV-based results further imply that the ligands XY perform as significant σ-donors but minor π-donors. The visual simulations of NOCV pairs and the deformation densities assemble a comprehensive summary on different components of the chemical bond via σ- and π-types in the complexes. This work contributes to the literature as an in-depth overview on predicted molecular structures and quantum parameters of the complexes [(CO)5W-X(YCp*)2] (X = Ge, Sn, Pb; Y = B-Tl), conducive to either further theoretical reference or extending experimental research.

Ultrathin hetero-nanosheets assembled hollow Ni-Co-P/C for hybrid supercapacitors with enhanced rate capability and cyclic stability.

Nanohybrid-type Ni-Co-phosphide/C (Ni-Co-P/C) hollow microflowers with ultrathin nanosheets (HUNs) are constructed through a modified ethylene glycol-mediated self-assembly process and further phosphating treatment. The peculiar structure can availably provide affluent mass transfer channels and active sites, meanwhile inhibit the aggregation of nanosheets. The synergistic effects of the produced Ni-Co-P/C are demonstrated systematically through regulating the initial Ni/Co ratio. A remarkable specific capacity of 205 mAh g-1 can be achieved at 1 A g-1, and the optimized Ni1-Co2-P/C (referred to as NiCoP/CoP/C) still holds a superior rate capability with a capacity retention of 71% even at 50 A g-1. Notably, the electrode also reveals an attractive capacity of 133 mAh g-1 with a high mass loading of 9.1 mg cm-2. A hybrid supercapacitor assembled with Ni1-Co2-P/C cathode and N-doped porous carbon anode demonstrates outstanding electrochemical performance, such as a high energy density (43 Wh kg-1 at a power density of 818 W kg-1) and excellent stability (90% retention after 20,000 cycles at 12 A g-1). The facile fabrication process and attractive performance make Ni1-Co2-P/C HUNs promising in energy storage applications.

cGMP Signaling in Cardiovascular Diseases: Linking Genotype and Phenotype.

Cyclic guanosine 3',5'-monophosphate (cGMP) is the key second messenger molecule in nitric oxide signaling. Its rapid generation and fate, but also its role in mediating acute cellular functions has been extensively studied. In the past years, genetic studies suggested an important role for cGMP in affecting the risk of chronic cardiovascular diseases, for example, coronary artery disease and myocardial infarction. Here, we review the role of cGMP in atherosclerosis and other cardiovascular diseases and discuss recent genetic findings and identified mechanisms. Finally, we highlight open questions and promising research topics.

Developing monitoring and evaluation tools for event-based surveillance: experience from Vietnam.

BACKGROUND: In 2016-2017, Vietnam's Ministry of Health (MoH) implemented an event-based surveillance (EBS) pilot project in six provinces as part of Global Health Security Agenda (GHSA) efforts. This manuscript describes development and design of tools for monitoring and evaluation (M&E) of EBS in Vietnam. METHODS: A strategic EBS framework was developed based on the EBS implementation pilot project's goals and objectives. The main process and outcome components were identified and included input, activities, outputs, and outcome indicators. M&E tools were developed to collect quantitative and qualitative data. The tools included a supervisory checklist, a desk review tool, a key informant interview guide, a focus group discussion guide, a timeliness form, and an online acceptability survey. An evaluation team conducted field visits for assessment of EBS 5-9 months after implementation. RESULTS: The quantitative data collected provided evidence on the number and type of events that were being reported, the timeliness of the system, and the event-to-signal ratio. The qualitative and subjective data collected helped to increase understanding of the system's field utility and acceptance by field staff, reasons for non-compliance with established guidelines, and other factors influencing implementation. CONCLUSIONS: The use of M&E tools for the EBS pilot project in Vietnam provided data on signals and events reported, timeliness of reporting and response, perceptions and opinions of implementers, and fidelity of EBS implementation. These data were valuable for Vietnam's MoH to understand the function of the EBS program, and the success and challenges of implementing this project in Vietnam.

Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis.

Aims: The efficacy and safety of oral semaglutide, the first glucagon-like peptide-1 (GLP-1) receptor agonist developed for oral administration for the treatment of type 2 diabetes, was evaluated in the PIONEER clinical trial program, and a recently published network meta-analysis allowed comparison with further injectable GLP-1 receptor agonists. The present study aimed to assess the short-term cost- effectiveness of oral semaglutide 14 mg versus subcutaneous once-weekly dulaglutide 1.5 mg, once-weekly exenatide 2 mg, twice-daily exenatide 10 µg, once-daily liraglutide 1.8 mg, once-daily lixisenatide 20 µg, and once-weekly semaglutide 1 mg, in terms of the cost per patient achieving glycated hemoglobin (HbA1c) targets (cost of control).Materials and methods: Cost of control was calculated by dividing the annual treatment costs associated with an intervention by the proportion of patients achieving the treatment target with an intervention, with outcomes calculated for targets of HbA1c ≤6.5% and HbA1c <7.0% for all included GLP-1 receptor agonists. Annual treatment costs were accounted in 2019 United States dollars (USD), based on 2019 wholesale acquisition cost.Results: For the treatment target of HbA1c ≤6.5%, once-weekly semaglutide 1 mg and oral semaglutide 14 mg were associated with the lowest costs of control, at USD 15,430 and USD 17,383 per patient achieving target, respectively. Similarly, the cost of control was lowest with once-weekly semaglutide 1 mg at USD 12,627 per patient achieving target, followed by oral semaglutide 14 mg at USD 13,493 per patient achieving target for the target of HbA1c <7.0%. All other interventions were associated with higher cost of control values for both targets.Conclusions: Oral semaglutide 14 mg is likely to be cost-effective versus dulaglutide, exenatide (once weekly and twice daily), liraglutide, and lixisenatide in terms of bringing people with type 2 diabetes to glycemic control targets of HbA1c ≤6.5% and HbA1c <7.0% in the US.