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Journal of Medical Ultrasonics (2001) Jun 2024Heart failure with preserved ejection fraction (HFpEF) accounts for nearly 70% of all HF and has become the dominant form of HF. The increased prevalence of HFpEF has... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) accounts for nearly 70% of all HF and has become the dominant form of HF. The increased prevalence of HFpEF has contributed to a rise in the number of HF patients, known as the "heart failure pandemic". In addition to the fact that HF is a progressive disease and a delayed diagnosis may worsen clinical outcomes, the emergence of disease-modifying treatments such as sodium-glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists has made appropriate and timely identification of HFpEF even more important. However, diagnosis of HFpEF remains challenging in patients with a lower degree of congestion. In addition to normal EF, this is related to the fact that left ventricular (LV) filling pressures are often normal at rest but become abnormal during exercise. Exercise stress echocardiography can identify such exercise-induced elevations in LV filling pressures and facilitate the diagnosis of HFpEF. Exercise stress echocardiography may also be useful for risk stratification and assessment of exercise tolerance as well as cardiovascular responses to exercise. Recent attention has focused on dedicated dyspnea clinics to identify early HFpEF among patients with unexplained dyspnea and to investigate the causes of dyspnea. This review discusses the role of exercise stress echocardiography in the diagnosis and evaluation of HFpEF.
PubMed: 38926301
DOI: 10.1007/s10396-024-01468-2 -
BMJ (Clinical Research Ed.) Jun 2024To evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl... (Comparative Study)
Comparative Study
SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study.
OBJECTIVES
To evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in routine clinical practice.
DESIGN
Population based cohort study with active-comparator, new user design.
SETTING
Claims data from Medicare and two large commercial insurance databases in the United States from April 2013 to April 2022.
PARTICIPANTS
1:1 propensity score matched adults with type 2 diabetes newly starting SGLT-2 inhibitors versus DPP-4 inhibitors (n=778 908), GLP-1 receptor agonists versus DPP-4 inhibitors (n=729 820), and SGLT-2 inhibitors versus GLP-1 receptor agonists (n=873 460).
MAIN OUTCOME MEASURES
Hyperkalemia diagnosis in the inpatient or outpatient setting. Secondary outcomes were hyperkalemia defined as serum potassium levels ≥5.5 mmol/L and hyperkalemia diagnosis in the inpatient or emergency department setting.
RESULTS
Starting SGLT-2 inhibitor treatment was associated with a lower rate of hyperkalemia than DPP-4 inhibitor treatment (hazard ratio 0.75, 95% confidence interval (CI) 0.73 to 0.78) and a slight reduction in rate compared with GLP-1 receptor agonists (0.92, 0.89 to 0.95). Use of GLP-1 receptor agonists was associated with a lower rate of hyperkalemia than DPP-4 inhibitors (0.79, 0.77 to 0.82). The three year absolute risk was 2.4% (95% CI 2.1% to 2.7%) lower for SGLT-2 inhibitors than DPP-4 inhibitors (4.6% 7.0%), 1.8% (1.4% to 2.1%) lower for GLP-1 receptor agonists than DPP-4 inhibitors (5.7% 7.5%), and 1.2% (0.9% to 1.5%) lower for SGLT-2 inhibitors than GLP-1 receptor agonists (4.7% 6.0%). Findings were consistent for the secondary outcomes and among subgroups defined by age, sex, race, medical conditions, other drug use, and hemoglobin A1c levels on the relative scale. Benefits for SGLT-2 inhibitors and GLP-1 receptor agonists on the absolute scale were largest for those with heart failure, chronic kidney disease, or those using mineralocorticoid receptor antagonists. Compared with DPP-4 inhibitors, the lower rate of hyperkalemia was consistently observed across individual agents in the SGLT-2 inhibitor (canagliflozin, dapagliflozin, empagliflozin) and GLP-1 receptor agonist (dulaglutide, exenatide, liraglutide, semaglutide) classes.
CONCLUSIONS
In people with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of hyperkalemia than DPP-4 inhibitors in the overall population and across relevant subgroups. The consistency of associations among individual agents in the SGLT-2 inhibitor and GLP-1 receptor agonist classes suggests a class effect. These ancillary benefits of SGLT-2 inhibitors and GLP-1 receptor agonists further support their use in people with type 2 diabetes, especially in those at risk of hyperkalemia.
Topics: Humans; Diabetes Mellitus, Type 2; Hyperkalemia; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Male; Female; Glucagon-Like Peptide-1 Receptor; Aged; Middle Aged; United States; Cohort Studies; Hypoglycemic Agents; Propensity Score; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38925801
DOI: 10.1136/bmj-2023-078483 -
AORN Journal Jul 2024Surgeons request intraoperative parathyroid hormone (PTH) monitoring during parathyroidectomy procedures to confirm identification of abnormal gland tissue. Generally, a...
Surgeons request intraoperative parathyroid hormone (PTH) monitoring during parathyroidectomy procedures to confirm identification of abnormal gland tissue. Generally, a 50% decrease in the baseline PTH level indicates the abnormal tissue has been removed. A delay in collecting and processing PTH blood samples can complicate intraoperative decision making and prolong the procedure. The purpose of this quality improvement project was to develop tools to facilitate the specimen management process (eg, requesting, transporting, analyzing) for PTH blood samples and decrease the average total time required for transit and assay. We implemented a two-pronged initiative that involved improving the laboratory requisition form and creating a parathyroid tote box to contain all the needed information and supplies. The average total time for transit and assay decreased from 31.36 minutes before implementation to 22.06 minutes after implementation. Perioperative nurses expressed satisfaction with the changes and continue to use the revised process.
Topics: Humans; Parathyroid Hormone; Parathyroidectomy; Specimen Handling; Quality Improvement
PubMed: 38925545
DOI: 10.1002/aorn.14162 -
Journal of Immunological Methods Jun 2024MHC class I pathway consists of four main steps: proteasomal cleavage in the cytosol in which precursor proteins are cleaved into smaller peptides, which are then...
MHC class I pathway consists of four main steps: proteasomal cleavage in the cytosol in which precursor proteins are cleaved into smaller peptides, which are then transported into the endoplasmic reticulum by the transporter associated with antigen processing, TAP, for further processing (trimming) from the N-terminal region by an ER resident aminopeptidases 1 (ERAP1) enzyme, to generate optimal peptides (8-10 amino acids in length) to produce a stable MHCI-peptide complex, that get transited via the Golgi apparatus to the cell surface for presentation to the cellular immune system. Several studies reported specificities related to the ERAP1 trimming process, yet there is no in silico tool for the prediction of the trimming process of the ERAP1 enzyme. In this paper, we provide and implement a prediction model for the trimming process of the ERAP1 enzyme.
PubMed: 38925438
DOI: 10.1016/j.jim.2024.113713 -
Biochemical and Biophysical Research... Jun 2024A hallmark of Alzheimer's disease (AD) is amyloid-β (Aβ) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AβOs), the...
A hallmark of Alzheimer's disease (AD) is amyloid-β (Aβ) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AβOs), the soluble precursor peptides producing Aβ plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AβOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AβOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AβOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AβOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AβOs or exosomes from 1 nM AβOs-treated- microglia or neurons, suggesting the implication of AβOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.
PubMed: 38924962
DOI: 10.1016/j.bbrc.2024.150312 -
Science Advances Jun 2024Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal...
Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.
Topics: Animals; Monocarboxylic Acid Transporters; Muscle, Skeletal; Symporters; Lactic Acid; Organelle Biogenesis; Mice; Citric Acid Cycle; Mitochondria; Sirtuin 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice, Knockout; Glycolysis
PubMed: 38924407
DOI: 10.1126/sciadv.adn4508 -
Journal of Diabetes Jul 2024Highlights A persistent glycosuria alongside hypoglycemia in pediatric type 1 diabetes mellitus needs further evaluation. Morning hypoglycemia is a limiting side effect...
Are sodium-glucose cotransporter-2 inhibitors safe adjunctive drugs during insulin therapy in young children with type 1 diabetes? The first case of type 1 diabetes with SLC5A2 mutation.
Highlights A persistent glycosuria alongside hypoglycemia in pediatric type 1 diabetes mellitus needs further evaluation. Morning hypoglycemia is a limiting side effect of sodium glucose transporter 2 (SGLT2) inhibitors in children younger than 5 years old. SLC5A2 mutation functioning as a SGLT2 inhibitor can result in acceptable range of glycated hemoglobin in younger children and lower required doses of insulin.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 1; Sodium-Glucose Transporter 2; Insulin; Mutation; Child, Preschool; Hypoglycemic Agents; Male; Blood Glucose; Female; Hypoglycemia; Glycated Hemoglobin; Drug Therapy, Combination
PubMed: 38923174
DOI: 10.1111/1753-0407.13570 -
Diabetes, Obesity & Metabolism Jun 2024To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus...
The efficacy and safety of iGlarLixi versus IDegAsp in Chinese people with type 2 diabetes suboptimally controlled with oral antidiabetic drugs: The Soli-D randomized controlled trial.
AIM
To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs).
METHODS
In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed.
RESULTS
At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported.
CONCLUSIONS
In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.
PubMed: 38922731
DOI: 10.1111/dom.15724 -
Toxins May 2024Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate... (Review)
Review
Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate (e.g., cell proliferation, dif-ferentiation, and apoptosis). The intricate balance in the PAs' levels in the tissues will determine whether beneficial or detrimental effects will affect homeostasis. It's crucial to note that endoge-nous polyamines, like spermine and spermidine, play a pivotal role in our understanding of neu-rological disorders as they interact with membrane receptors and ion channels, modulating neuro-transmission. In spiders and wasps, monoamines (histamine, dopamine, serotonin, tryptamine) and polyamines (spermine, spermidine, acyl polyamines) comprise, with peptides and other sub-stances, the low molecular weight fraction of the venom. Acylpolyamines are venom components exclusively from spiders and a species of solitary wasp, which cause inhibition chiefly of iono-tropic glutamate receptors (AMPA, NMDA, and KA iGluRs) and nicotinic acetylcholine receptors (nAChRs). The first venom acylpolyamines ever discovered (argiopines, Joro and Nephila toxins, and philanthotoxins) have provided templates for the design and synthesis of numerous analogs. Thus far, analogs with high potency exert their effect at nanomolar concentrations, with high se-lectivity toward their ionotropic and ligand receptors. These potent and selective acylpolyamine analogs can serve biomedical purposes and pest control management. The structural modification of acylpolyamine with photolabile and fluorescent groups converted these venom toxins into use-ful molecular probes to discriminate iGluRs and nAchRs in cell populations. In various cases, the linear polyamines, like spermine and spermidine, constituting venom acyl polyamine backbones, have served as cargoes to deliver active molecules via a polyamine uptake system on diseased cells for targeted therapy. In this review, we examined examples of biogenic amines that play an essential role in neural homeostasis and cell signaling, contributing to human health and disease outcomes, which can be present in the venom of arachnids and hymenopterans. With an empha-sis on the spider and wasp venom acylpolyamines, we focused on the origin, structure, derivatiza-tion, and biomedical and biotechnological application of these pharmacologically attractive, chemically modular venom components.
Topics: Animals; Polyamines; Spider Venoms; Insecticides; Wasps; Humans; Spiders
PubMed: 38922129
DOI: 10.3390/toxins16060234 -
Insects Jun 2024The ectoparasitoid (Hymenoptera: Braconidae) exhibits a broad parasitic capability towards various lepidopteran pests, with venom serving as a crucial virulent factor...
The ectoparasitoid (Hymenoptera: Braconidae) exhibits a broad parasitic capability towards various lepidopteran pests, with venom serving as a crucial virulent factor ensuring successful parasitization and subsequent host mortality. Analyzing the constituents of its venom is essential for elucidating the mechanisms underlying efficient host killing by this parasitoid and for exploring potentially functional venom proteins. Through a transcriptomic analysis, a total of 34 venom proteins were identified within the venom of , encompassing known components such as serine protease, metalloproteinase, esterase, and serine protease inhibitors commonly present in parasitoid venoms. Unique components like paralytic protein and ion transport peptide-like were identified, possibly specific to certain parasitoids, along with novel proteins with uncharacterized functions. Spatial gene expression profiling of the identified venom proteins using transcriptomic data, corroborated by quantitative PCR validation for 13 randomly selected proteins, revealed abundant expression levels in the venom apparatus, affirming them as genuine venom components. Notably, the paralytic protein exhibited prominent expression, with the highest FPKM (fragments per kilobase of transcript per million fragments mapped) value of 24,704.87 in the venom apparatus, indicative of its significant role in successful parasitism by . The identification of these venom proteins establishes a foundation for the further exploration of bioactive agents for pest management strategies.
PubMed: 38921141
DOI: 10.3390/insects15060426