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Cardiovascular diseases (CVDs) are one of the foremost causes of high morbidity and mortality globally. Preventive, diagnostic, and treatment measures available for CVDs are not very useful, which demands promising alternative methods. Nanoscience and nanotechnology open a new window in the area of CVDs with an opportunity to achieve effective treatment, better prognosis, and less adverse effects on non-target tissues. The application of nanoparticles and nanocarriers in the area of cardiology has gathered much attention due to the properties such as passive and active targeting to the cardiac tissues, improved target specificity, and sensitivity. It has reported that more than 50% of CVDs can be treated effectively through the use of nanotechnology. The main goal of this review is to explore the recent advancements in nanoparticle-based cardiovascular drug carriers. This review also summarizes the difficulties associated with the conventional treatment modalities in comparison to the nanomedicine for CVDs.

Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (≥18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA1c 7·9% [63 mmol/mol], age 54·1 years [SD 11·9], 231 [48%] women, diabetes duration 4·7 years, and body-mass index 31·9 kg/m2) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA1c, fasting serum glucose, bodyweight, and HbA1c targets of less than 7·0% (<53 mmol/mol) and less than 5·7% (<39 mmol/mol). Mean HbA1c decreased from baseline by 1·87% (20 mmol/mol) with tirzepatide 5 mg, 1·89% (21 mmol/mol) with tirzepatide 10 mg, and 2·07% (23 mmol/mol) with tirzepatide 15 mg versus +0·04% with placebo (+0·4 mmol/mol), resulting in estimated treatment differences versus placebo of −1·91% (−21 mmol/mol) with tirzepatide 5 mg, −1·93% (−21 mmol/mol) with tirzepatide 10 mg, and −2·11% (−23 mmol/mol) with tirzepatide 15 mg (all p<0·0001). More participants on tirzepatide than on placebo met HbA1c targets of less than 7·0% (<53 mmol/mol; 87–92% vs 20%) and 6·5% or less (≤48 mmol/mol; 81–86% vs 10%) and 31–52% of patients on tirzepatide versus 1% on placebo reached an HbA1c of less than 5·7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7·0 to 9·5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12–18% vs 6%), diarrhoea (12–14% vs 8%), and vomiting (2–6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. Eli Lilly and Company.

Background. Most information on bone-joint (BJ)-tuberculosis is based on data from high-incidence areas. We conducted a nationwide register-based analysis of BJ-tuberculosis in Denmark from 1994 to 2011. Methods. We linked data from the national tuberculosis surveillance system on BJ-tuberculosis, hospital records, the Danish Hospital and Civil Registration System. Results. We identified 282 patients with BJ-tuberculosis, 3.6% of all tuberculosis cases (n = 7936). Spinal tuberculosis was found in 153 of 282 patients (54.3%); 83.3% of all cases were immigrants. Danes were older and had higher Charlson comorbidity index scores than immigrants (P < .01). C-reactive protein and erythrocyte sedimentation rates were elevated in most cases. Median time to diagnosis after first hospital contact was 19.5 days for spinal tuberculosis and 28 days for other forms of BJ-tuberculosis (P = .01). Of patients with spinal tuberculosis, 54/133 (40.6%) had neurologic deficits at admission and 17.3% presented with cauda equina. Diagnosis was culture verified in 87%. (Resistance to any drug was found in 10.2%). Median time on antituberculous treatment for patients with spinal and other forms of BJ-tuberculosis was 9 months and 7 months, respectively (P < .01). Surgery was required in 44.4% patients with spinal tuberculosis and in 32.6% patients with other forms of BJ-tuberculosis (P = .04). Sequelae were reported in 57.5% of patients with spinal tuberculosis and 29.1% of patient with other forms of BJ-tuberculosis (P < .01). One-year mortality was 25.5% among Danes compared with 1.3% among immigrants (P < .01). Conclusions. BJ-tuberculosis was rare and seen mainly in younger immigrants in Denmark. More than half of cases were spinal tuberculosis, presenting with more severe symptoms and worse outcome, compared with other forms of BJ-tuberculosis.

Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.

Interactions between ceria (CeO 2 ) and supported metals greatly enhance rates for a number of important reactions. However, direct relationships between structure and function in these catalysts have been difficult to extract because the samples studied either were heterogeneous or were model systems dissimilar to working catalysts. We report rate measurements on samples in which the length of the ceria-metal interface was tailored by the use of monodisperse nickel, palladium, and platinum nanocrystals. We found that carbon monoxide oxidation in ceria-based catalysts is greatly enhanced at the ceria-metal interface sites for a range of group VIII metal catalysts, clarifying the pivotal role played by the support.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being. Genome-wide association analyses identify 57 loci associated with insomnia symptoms and provide evidence of shared genetic architecture between insomnia and cardiometabolic, behavioral, psychiatric and reproductive traits.

The concept of fiscal decentralisation is explained to be central to all models of decentralisation of public services to subnational governments. Fiscal decentralisation is generally referred to as the transfer of budget powers in terms of revenue and expenditure from national to subnational governments. Although fiscal decentralisation aims to ensure local financial independence, subnational governments continually experience financial shortfalls. In this regard, intergovernmental fiscal transfers are considered to address the financial gaps and guarantee continuity of public service delivery at subnational spheres of government. To understand transfers, the paper reviews the concept of intergovernmental transfers and explores the nature of the Lesotho intergovernmental transfer system. The study on which the article is based adopted the convergent mixed methodology. The findings indicate that Lesotho uses transfers as the primary source of revenue for subnational structures. Therefore, Lesotho subnational governments depend on transfers as their sole source of revenue, and this constrains the capacity of subnational governments to deliver services. The country does not have an intergovernmental fiscal transfer framework designed to regulate and direct transfers between and among government spheres. The article, therefore, recommends a three-pronged framework that considers the development of a subnational financial management legislative framework that demarcates the subnational financial scope and guides the subnational financial practices and processes; a decision by the country on the degree of revenue devolution to activate local revenue generation; and developing an intergovernmental transfer system based on revenue generation capacity and spending needs of councils to ensure incentive compatibility and secure some degree of equity among districts.

PurposeThe aim of the present study was to assess the impact of the daily consumption of bread enriched with hydroxytyrosol on HbA1c and blood lipid levels, inflammatory markers and weight loss.MethodsSixty adults with overweight/obesity and type 2 diabetes mellitus (29 male, 31 female) participated in a 12-week dietary intervention based on the Mediterranean diet and consumed daily 60 g of conventional whole wheat bread (WWB) or whole wheat bread enriched with hydroxytyrosol (HTB). Anthropometric characteristics were measured and venous blood samples were collected at baseline and at the end of the intervention.ResultsBoth groups experienced significant weight loss, body fat and waist circumference decrease (p < 0.001). Nonetheless, a greater body fat mass decrease was observed in the HTB group compared to the WWB group (14.4 ± 1.6 vs 10.2 ± 1.1%, p = 0.038). Significant reductions were also reported in fasting glucose, HbA1c and blood pressure in both groups (p < 0.05). Regarding glucose and HbA1c, greater decreases were observed in the intervention group (101.4 ± 19.9 vs. 123.2 ± 43.4 mg/dL, p = 0.015 and 6.0 ± 0.6 vs. 6.4 ± 0.9%, p = 0.093, respectively). At HTB group, significant reductions in blood lipid, insulin, TNF-αand adiponectin levels (p < 0.05) and a marginally significant reduction in leptin levels (p = 0.081) were also reported.ConclusionEnrichment of bread with HT resulted in significant body fat mass reduction and positive effects on fasting glucose, insulin and HbA1c levels. It also contributed to reductions in inflammatory markers and blood lipid levels. Incorporation of HT in staple foods, like bread, may improve their nutritional profile and, in terms of a balanced diet, may contribute to the management of chronic diseases.Trial registrationThe study was prospectively registered in clinicaltrials.gov (24th May 2021). ClinicalTrials.gov Identifier: NCT04899791.

Abstract Objectives Almost half of all patients diagnosed with uveal melanoma will die of metastatic disease. This has been attributed to early seeding of micrometastases. We investigate the presence, density, organ involvement, and characteristics of micrometastases of uveal melanoma in tissue obtained at autopsy of patients with and without coexisting macrometastases. Methods Patients diagnosed with primary uveal melanoma at a national referral center between 1960 and 2020 (n = 4,282) were cross-referenced with autopsy registers at nearby hospitals. Eleven patients were included. Formalin-fixed, paraffin-embedded tissue samples obtained during autopsy were examined with routine histology, immunohistochemistry, and immunomagnetic separation. Results Micrometastases were detected in 5 of 5 patients with and in 5 of 6 patients without coexisting macrometastases. Micrometastases were identified in several sites, including lungs, kidneys, myocardium, and bone marrow. Their highest density per mm2 of tissue was seen in the liver. Of 11 examined patients, 2 had at least 1 BAP-1–positive metastasis. All micrometastases had immune cell infiltrates and no or very low proliferative activity. Conclusions We demonstrate multiorgan involvement of apparently dormant micrometastases in patients with uveal melanoma. This suggests that micrometastases are present in nearly all patients diagnosed with primary uveal melanoma, regardless of coexisting macrometastases.

As the global population rises, the dependency on edible oils also rises. The used oil possesses environmental concerns due to improper waste oil disposal. This study emphasises the feasibility of repurposing waste cooking oil (WCO) for eco-friendly lubricating grease production, emphasising enhanced stability and performance through chemical modifications. Chemical modifications, primarily transesterification, enhance the oxidative stability and chemical properties of WCO. Gas chromatography and mass spectroscopy analyse the fatty acid profile, and the hot oil oxidation test (HOOT) assesses the oxidative characteristics of WCO. The formulated grease using WCO undergoes tribological testing and penetration value testing. Results indicate post-transesterification improvements in chemical and oxidative stability, with lowered acid and peroxide values. Modified waste cooking oil (MWCO) exhibits enhanced thermal stability with higher flash and fire points. Viscosity results suggest the potential of MWCO as a lubricant with superior oxidative stability. Tribological properties reveal an improved characteristic value for MWCO, establishing its potential as an eco-friendly grease. Cone penetration tests categorise the formulated grease as NLGI grade 2, indicating a softer consistency with potential advantages for specific applications. The findings offer insights into the sustainable development of the lubricant industry, presenting MWCO as a promising alternative to conventional lubricants.