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The Time-Varying Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Patients with Type 2 Diabetes Mellitus: Evidence from Large Multinational Trials
Get PDFAims: To evaluate the time-varying cardio-protective effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate. Material and Methods: Data from eight multinational cardiovascular outcome randomized controlled trials of GLP-1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan-Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance-weighted random-effects model; heterogeneity was tested with Cochran\u27s Q statistic. The endpoints studied were: three-point major adverse cardiovascular events (MACE), all-cause mortality, stroke, cardiovascular mortality and myocardial infarction. Results: We included eight large (3183-14 752 participants, total = 60 080; median follow-up range: 1.5 to 5.4 years) GLP-1RA trials. Among GLP-1RA recipients, we observed an average delay in three-point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [−0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08-0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15-0.33]) in patients receiving GLP-1RAs. Conclusions: Glucagon-like peptide-1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment
The Relationship Between Anti-Müllerian Hormone, Body Mass Index and Weight Loss: A Review of the Literature
No full textAnti-Müllerian hormone (AMH) is commonly used as a proxy for ovarian reserve due to its secretion by antral follicles. It is considered a metric for prediction of ovarian response to certain assisted reproduction therapies. As obesity has a negative impact on fertility, it is important to establish whether obesity-induced hormonal changes influence AMH levels, if and how weight loss affects AMH, and if that influence represents altered reproductive function. The aim of this study was to review the existing literature on the effects of body mass index and weight loss on AMH levels. A PubMed literature keyword search with relevant terms was performed to identify studies that have reported on the AMH/BMI relationship in cohorts with or without polycystic ovarian syndrome (PCOS). A second search was performed to gather publications on weight loss and AMH. Both searches were filtered for all full-text, English-language, adult-female and human-only literature through 1 January 2022. The relationship between AMH and body mass index (BMI) in reproductive-aged women remains inconclusive, with studies in women with and without PCOS producing mixed results. Research in this area is currently limited by failure to analyse the full spectrum of obesity, hindering generalization to a global population increasingly affected by the condition. Some authors pointed to evidence of race/ethnicity as a confounding factor of the relationship, but results between studies are contradictory. Limited evidence on weight loss suggests it may decrease AMH levels despite improving fertility outcomes, particularly after bariatric surgery. The impact of BMI and weight loss on AMH levels has not been conclusively established. Future studies will require appropriate design and sample size calculations, consideration for additional potential confounding factors and inclusion of higher BMIs and a thorough analysis of the full range of obesity
Neuroinflammatory Gene Expression Analysis Reveals Pathways of Interest as Potential Targets to Improve the Recording Performance of Intracortical Microelectrodes
Get PDFIntracortical microelectrodes are a critical component of brain-machine interface (BMI) systems. The recording performance of intracortical microelectrodes used for both basic neuroscience research and clinical applications of BMIs decreases over time, limiting the utility of the devices. The neuroinflammatory response to the microelectrode has been identified as a significant contributing factor to its performance. Traditionally, pathological assessment has been limited to a dozen or so known neuroinflammatory proteins, and only a few groups have begun to explore changes in gene expression following microelectrode implantation. Our initial characterization of gene expression profiles of the neuroinflammatory response to mice implanted with non-functional intracortical probes revealed many upregulated genes that could inform future therapeutic targets. Emphasis was placed on the most significant gene expression changes and genes involved in multiple innate immune sets, including Cd14, C3, Itgam, and Irak4. In previous studies, inhibition of Cluster of Differentiation 14 (Cd14) improved microelectrode performance for up to two weeks after electrode implantation, suggesting CD14 can be explored as a potential therapeutic target. However, all measures of improvements in signal quality and electrode performance lost statistical significance after two weeks. Therefore, the current study investigated the expression of genes in the neuroinflammatory pathway at the tissue-microelectrode interface in Cd14−/− mice to understand better how Cd14 inhibition was connected to temporary improvements in recording quality over the initial 2-weeks post-surgery, allowing for the identification of potential co-therapeutic targets that may work synergistically with or after CD14 inhibition to improve microelectrode performance
Disclosing the Role of C4-Oxo Substitution in the Photochemistry of DNA and RNA Pyrimidine Monomers: Formation of Photoproducts from the Vibrationally Excited Ground State
Get PDFOxo and amino substituted purines and pyrimidines have been suggested as protonucleobases participating in ancient pre-RNA forms. Considering electromagnetic radiation as a key environmental selection pressure on early Earth, the investigation of the photophysics of modified nucleobases is crucial to determine their viability as nucleobases’ ancestors and to understand the factors that rule the photostability of natural nucleobases. In this Letter, we combine femtosecond transient absorption spectroscopy and quantum mechanical simulations to reveal the photochemistry of 4-pyrimidinone, a close relative of uracil. Irradiation of 4-pyrimidinone with ultraviolet radiation populates the S1(ππ*) state, which decays to the vibrationally excited ground state in a few hundred femtoseconds. Analysis of the postirradiated sample in water reveals the formation of a 6-hydroxy-5H-photohydrate and 3-(N-(iminomethyl)imino)propanoic acid as the primary photoproducts. 3-(N-(Iminomethyl)imino)propanoic acid originates from the hydrolysis of an unstable ketene species generated from the C4-N3 photofragmentation of the pyrimidine core
An Implementation Roadmap for Establishing Remote Infectious Disease Specialist Support for Consultation and Antibiotic Stewardship in Resource-Limited Settings
Get PDFInfectious Disease (ID)-trained specialists, defined as ID pharmacists and ID physicians, improve hospital care by providing consultations to patients with complicated infections and by leading programs that monitor and improve antibiotic prescribing. However, many hospitals and nursing homes lack access to ID specialists. Telehealth is an effective tool to deliver ID specialist expertise to resource-limited settings. Telehealth services are most useful when they are adapted to meet the needs and resources of the local setting. In this step-by-step guide, we describe how a tailored telehealth program can be implemented to provide remote ID specialist support for direct patient consultation and to support local antibiotic stewardship activities. We outline 3 major phases of putting a telehealth program into effect: pre-implementation, implementation, and sustainment. To increase the likelihood of success, we recommend actively involving local leadership and other stakeholders in all aspects of developing, implementing, measuring, and refining programmatic activities
Catch Bonds in Sickle Cell Disease: Shear-Enhanced Adhesion of Red Blood Cells to Laminin
Get PDFCould the phenomenon of catch bonding—force-strengthened cellular adhesion—play a role in sickle cell disease, where abnormal red blood cell (RBC) adhesion obstructs blood flow? Here we investigate the dynamics of sickle RBCs adhering to a surface functionalized with the protein laminin (a component of the extracellular matrix around blood vessels) under physiologically relevant micro-scale flow. First, using total internal reflectance microscopy we characterize the spatial fluctuations of the RBC membrane above the laminin surface before detachment. The complex dynamics we observe suggest the possibility of catch bonding, where the mean detachment time of the cell from the surface initially increases to a maximum and then decreases as a function of shear force. We next conduct a series of shear-induced detachment experiments on blood samples from 25 sickle cell disease patients, quantifying the number and duration of adhered cells under both sudden force jumps and linear force ramps. The experiments reveal that a subset of patients does indeed exhibit catch bonding. By fitting the data to a theoretical model of the bond dynamics, we can extract the mean bond lifetime versus force for each patient. The results show a striking heterogeneity among patients, both in terms of the qualitative behavior (whether or not there is catch bonding) and in the magnitudes of the lifetimes. Patients with large bond lifetimes at physiological forces are more likely to have certain adverse clinical features, like a diagnosis of pulmonary arterial hypertension and intracardiac shunts. By introducing an in vitro platform for fully characterizing RBC-laminin adhesion dynamics, our approach could contribute to the development of patient-specific anti-adhesive therapies for sickle cell disease. The experimental setup is also easily generalizable to studying adhesion dynamics in other cell types, for example leukocytes or cancer cells, and can incorporate disease-relevant environmental conditions like oxygen deprivation
Anti‐CD20 Therapeutic Options in Immune‐Mediated Thrombotic Thrombocytopenic Purpura
Get PDFImmunosuppression with rituximab in immune-mediated thrombotic thrombocytopenic purpura helps decrease production of autoantibody mediating ADAMTS13 clearance from circulation. Failure to respond to rituximab in a satisfactory way or made difficult by adverse events to the medication does not represent a reason to stop considering anti-CD20 therapies to control antibody production. Therefore, both of atumumab and obinutuzumab with specificity to CD20, represent potentially valuable therapeutic tools in patients who are not candidates for rituximab. Commentary on: Doyle et al. The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura. Br J Haematol. 2022;198:391-396.1
Prediction of Neonatal Growth Restriction in Fetuses with Gastroschisis by Early Third Trimester Ultrasonography Utilizing Contemporary Birth Weight Percentiles
Get PDFObjective: To identify the estimated fetal weight (EFW) formula and threshold for the optimal prediction of fetal growth restriction (FGR) at 26–34 weeks\u27 in fetuses with gastroschisis. Methods: Late second and third trimester ultrasound data were used to calculate the EFW utilizing eight different formulas: Hadlock I-IV, Honarvar, Shepard, Siemer, and Warsof. EFW and birth weight percentiles were assigned from US population growth curves. FGR and small for gestational age (SGA) were defined as EFW and birth weight less than the tenth percentile for gestational age; Receiver operating characteristic (ROC) curves were used to compare formula performance for FGR diagnosis at 26–34 weeks\u27 to identify an SGA birth weight. Results: There were 170 newborns with gastroschisis; 46 (27%) were SGA. The mean gestational age at the time of ultrasound was 30.8 ± 1.7 weeks. The mean gestational age at birth was 36.3 ± 1.7 weeks. ROC curve analysis found the Hadlock III formula had the largest area under the curve (AUC) of 0.813 closely followed by Hadlock IV (AUC = 0.811) and Hadlock II (AUC = 0.808) for diagnosis of FGR correlating to neonatal SGA diagnosis. Hadlock II, Hadlock III, and Hadlock IV had the highest diagnostic accuracies when compared to the other EFW formulas. Conclusions: The Hadlock II, Hadlock III, and Hadlock IV formulas have comparable predictive performance in the optimal identification of FGR in fetuses with gastroschisis at 26–34 weeks\u27. A threshold of an EFW less than the 25.2th percentile is suggested
Comparing Learning Retention in Medical Students Using Mixed-Reality to Supplement Dissection: A Preliminary Study
Get PDFObjectives: To evaluate student impressions of learning anatomy with mixed-reality and compare long-term information retention of female breast anatomy between students who learned with a mixed-reality supplement and their classmates who dissected cadavers. Methods: In Part 1, 38 first-year medical student volunteers, randomly divided into two groups, completed a mixed-reality module and cadaveric dissection on the female breast in a counterbalanced design. Participants also completed post-quizzes and surveys. Part 2 was a non-randomized controlled trial, 8-months after completing Part 1 and 6-months after a final exam on this content. The performance of twenty-two Part 1 participants and 129 of their classmates, who only dissected, was compared on a delayed post-quiz. Wilcoxon signed-rank test, Mann-Whitney U test, and 95% confidence intervals were used to analyze the data. Results: In Part 1, the Wilcoxon signed-rank test determined that participants expressed significantly more positive responses to mixed-reality and found mixed-reality easier for learning and teamwork. In Part 2, the Mann-Whitney U test found mixed-reality participants scored significantly higher on a delayed-post quiz than their classmates who only dissected (U = 928, p \u3c .009). Conclusions: This study suggests that medical students may prefer mixed-reality and that it may be an effective modality for learning breast anatomy while facilitating teamwork. Results also suggest that supplementing cadaveric dissection with mixed-reality may improve long-term retention for at least one anatomical topic. It is recommended that similar studies evaluate a larger sample and additional anatomical regions to determine the generalizability of these findings
Grafting of Short Elastin-Like Peptides Using an Electric Field
Get PDFSurface-grafted elastin has found a wide range of uses such as sensing, tissue engineering and capture/release applications because of its ability to undergo stimuli-responsive phase transition. While various methods exist to control surface grafting in general, it is still difficult to control orientation as attachment occurs. This study investigates using an electric field as a new approach to control the surface-grafting of short elastin-like polypeptide (ELP). Characterization of ELP grafting to gold via quartz crystal microbalance with dissipation, atomic force microscopy and temperature ramping experiments revealed that the charge/hydrophobicity of the peptides, rearrangement kinetics and an applied electric field impacted the grafted morphology of ELP. Specifically, an ELP with a negative charge on the opposite end of the surface-binding moiety assembled in a more upright orientation, and a sufficient electric field pushed the charge away from the surface compared to when the same peptide was assembled in no electric field. In addition, this study demonstrated that assembling charged ELP in an applied electric field impacts transition behavior. Overall, this study reveals new strategies for achieving desirable and predictable surface properties of surface-bound ELP
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