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1.
Cardiorenal Med ; 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38934134

ABSTRACT

BACKGROUND: Studies exploring the effectiveness and safety of percutaneous left atrial appendage occlusion (pLAAO) in patients with chronic kidney disease (CKD) are limited. OBJECTIVES: We aimed to analyze trends and outcomes following pLAAO in patients with CKD. METHODS: We utilized the National Inpatient Sample (NIS) to identify hospitalizations for pLAAO from 2016-2020 and further identified cases with concomitant CKD. The primary outcome was mortality, and secondary outcomes were cerebrovascular accidents, major bleeding, vasopressor requirements, percutaneous coronary intervention, cardiac arrest, acute respiratory failure, transfusion, length of stay (LOS), and total hospital charges. Multivariable logistic regression was performed to further adjust for covariates. RESULTS: A total of 89,309 pLAAO procedures from 2016 to 2020 were identified, of which 21,559 (24.1%) reported concomitant CKD, with males comprising the majority (62.2%). An increasing trend in pLAAO procedures was seen from 2.24 to 13.9 per 10,000 patients from 2016 to 2020. Despite patients with CKD having a higher rate of most comorbidities, there was no difference in mortality (non-CKD vs. CKD, 0.07% vs. 0.42%; aOR: 1.3, 95% CI: 0.4 - 4.4, p=0.686) and complications for CKD and non-CKD patients, while CKD patients had longer LOS and higher total hospital charge. No significant sex differences in outcomes among CKD patients were observed except for a longer LOS in females. CONCLUSION: Despite generally having more comorbidities, outcomes of patients with CKD following pLAAO are similar to those without CKD, suggesting that pLAAO can be offered as a safe option for the treatment of AF in eligible patients with CKD.

2.
J Clin Lipidol ; 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38906751

ABSTRACT

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been pivotal in the management of type 2 diabetes mellitus (T2DM) and in the reduction of major adverse cardiovascular events (MACE). Notably, large cardiovascular outcomes trials (CVOTs) demonstrate significant disparities in inclusion, based on sex, race, ethnicity, and geographical regions. OBJECTIVES: We examined the impact of GLP-1RA on MACE in patients with or without T2DM, based on sex, race, ethnicity, and geography. METHODS: A literature search for placebo controlled RCTs on GLP-1RA treatment was conducted. Thorough data extraction and quality assessment were carried out, focusing on key outcome, and ensuring a robust statistical analysis using a random effects model to calculate log odds ratio with 95% confidence intervals (CIs). RESULTS: A total of 8 CVOTs comprising 71,616 patients were included. Compared with placebo, GLP-1RAs significantly reduced MACE in both sexes (females: logOR -0.19, (95% CI, -0.28 to -0.10), p < 0.01] versus males: logOR -0.17, 95% CI, -0.23 to -0.10), p < 0.01], (p interaction NS)], and among Asians (logOR -34 (95% CI, -0.53 to -0.15, p < 0.01), and Whites (logOR -17 (95% CI, -0.25 to -0.09, p < 0.01), with no difference in MACE among Blacks and Hispanics. Odds of MACE were also reduced in Asia (logOR -31 (95% CI, -0.50 to -0.11, p < 0.01), and Europe (logOR -27 (95% CI, -0.40 to -0.13, p < 0.01), but there was no statistical difference in MACE in North America and Latin America. CONCLUSION: Significant reductions in MACE with GLP-1RA treatment were demonstrated between both sexes and across certain ethnicities and certain geographical regions.

3.
Curr Med Res Opin ; 40(7): 1103-1121, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38836510

ABSTRACT

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.


Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , PCSK9 Inhibitors , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Humans , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Female , Proprotein Convertase 9/metabolism , Male , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic use , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology
4.
Heart Lung ; 67: 144-151, 2024.
Article in English | MEDLINE | ID: mdl-38762962

ABSTRACT

BACKGROUND: Despite comprising almost half of all patients undergoing valvular repair, data on transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis (BAS) are limited. OBJECTIVE: We aimed to evaluate whether there are any sex differences in trends and outcomes of TAVR in this population. METHODS: We utilized the National Inpatient Sample from 2012 to 2020 to identify admissions with BAS who underwent TAVR and analyzed trends and outcomes. Our primary outcome was in-hospital mortality and secondary outcomes were in-hospital complications. We used two models to adjust for demographics (A) and interventions (B). RESULTS: Between 2012 to 2020, there were 76,540 hospitalizations for BAS patients who underwent AVR, among which 6,010 (7.9 %) underwent TAVR. There was an overall increasing trend in number of TAVR cases with a decreasing trend in mortality (2013: 8.7 %, 2020: 1.3 %). TAVR was performed more in males (61.1% vs 38.9 %). Despite the worse baseline characteristics in males, in-hospital mortality (2.4% vs. 1.5 %; OR: 1.584; 95 % CI: 0.621-4.038; p = 0.335) and secondary outcomes were similar across both sexes, even after adjusting for demographics and interventions. CONCLUSION: TAVR in BAS has grown rapidly in the last decade. Males comprised the majority and had more comorbidities, but mortality and complications were similar in both sexes. Despite the increasing number of cases, a decreasing trend in mortality was observed for both sexes ultimately approaching that of SAVR, suggesting that TAVR may be a safe alternative among eligible males and females with bicuspid AS.


Subject(s)
Aortic Valve Stenosis , Bicuspid Aortic Valve Disease , Hospital Mortality , Transcatheter Aortic Valve Replacement , Humans , Transcatheter Aortic Valve Replacement/methods , Transcatheter Aortic Valve Replacement/statistics & numerical data , Transcatheter Aortic Valve Replacement/adverse effects , Male , Female , Aortic Valve Stenosis/surgery , Aortic Valve Stenosis/epidemiology , Aortic Valve Stenosis/complications , Bicuspid Aortic Valve Disease/surgery , Bicuspid Aortic Valve Disease/complications , Hospital Mortality/trends , Aged , Sex Factors , United States/epidemiology , Aged, 80 and over , Retrospective Studies , Postoperative Complications/epidemiology , Treatment Outcome , Aortic Valve/surgery , Aortic Valve/abnormalities , Risk Factors , Heart Valve Diseases/surgery , Heart Valve Diseases/complications
5.
Article in English | MEDLINE | ID: mdl-38780827

ABSTRACT

This paper reports the findings of a Canada based multi-institutional study designed to investigate the relationships between admissions criteria, in-program assessments, and performance on licensing exams. The study's objective is to provide valuable insights for improving educational practices across different institutions. Data were gathered from six medical schools: McMaster University, the Northern Ontario School of Medicine University, Queen's University, University of Ottawa, University of Toronto, and Western University. The dataset includes graduates who undertook the Medical Council of Canada Qualifying Examination Part 1 (MCCQE1) between 2015 and 2017. The data were categorized into five distinct sections: demographic information as well as four matrices: admissions, course performance, objective structured clinical examination (OSCE), and clerkship performance. Common and unique variables were identified through an extensive consensus-building process. Hierarchical linear regression and a manual stepwise variable selection approach were used for analysis. Analyses were performed on data set encompassing graduates of all six medical schools as well as on individual data sets from each school. For the combined data set the final model estimated 32% of the variance in performance on licensing exams, highlighting variables such as Age at Admission, Sex, Biomedical Knowledge, the first post-clerkship OSCE, and a clerkship theta score. Individual school analysis explained 41-60% of the variance in MCCQE1 outcomes, with comparable variables to the analysis from of the combined data set identified as significant independent variables. Therefore, strongly emphasising the need for variety of high-quality assessment on the educational continuum. This study underscores the importance of sharing data to enable educational insights. This study also had its challenges when it came to the access and aggregation of data. As such we advocate for the establishment of a common framework for multi-institutional educational research, facilitating studies and evaluations across diverse institutions. This study demonstrates the scientific potential of collaborative data analysis in enhancing educational outcomes. It offers a deeper understanding of the factors influencing performance on licensure exams and emphasizes the need for addressing data gaps to advance multi-institutional research for educational improvements.

6.
Am J Prev Cardiol ; 18: 100679, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38779187

ABSTRACT

Background: Multiple cardiovascular outcomes trials (CVOTs) have shown the efficacy of GLP-1RAs in reducing major adverse cardiovascular events (MACEs) for high-risk patients. However, some CVOTs failed to demonstrate cardiovascular benefits. Objectives: We analyzed the impact of GLP-1RA on cardiovascular and renal outcomes in patients with or without T2DM, with subgroup analysis based on sex, estimated glomerular filtration rate (eGFR), body mass index (BMI), and history of cardiovascular disease (CVD). Methods: A comprehensive database search for placebo-controlled RCTs on GLP-1RA treatment was conducted until April 2024. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with log odds ratios and 95 % confidence intervals (CIs). Results: A total of 13 CVOTs comprising 83,258 patients were included. GLP-1RAs significantly reduced MACE (OR 0.86, 95 % CI: 0.80 to 0.94, p < 0.01) all-cause mortality OR 0.87, 95 % CI: 0.82 to 0.93, p < 0.001, CV mortality (OR 0.87, 95 % CI: 0.81 to 0.94, p < 0.001), stroke (fatal: OR 0.74, 95 % CI: 0.56 to 0.96, p = 0.03; non-fatal: OR 0.87, 95 % CI: 0.79 to 0.96, p = 0.005), coronary revascularization (OR 0.86, 95 % CI: 0.74 to 0.99, p = 0.023), and composite kidney outcome (OR 0.76, 95 % CI: 0.67 to 0.85, p < 0.001. GLP-1RA significantly reduced MACE in both sexes. Furthermore, GLP-1RA reduced MACE regardless of CVD history, BMI, and eGFR level. Conclusion: Significant reductions in MACE, overall and CV mortality, stroke, coronary revascularization, and composite kidney outcome with GLP-1RA treatment were noted across all subgroups.

7.
Expert Rev Cardiovasc Ther ; 22(4-5): 193-200, 2024.
Article in English | MEDLINE | ID: mdl-38459907

ABSTRACT

BACKGROUND: Sex differences in clinical outcomes following acute myocardial infarction (AMI) are well known. However, data on sex differences among patients with familial hypercholesterolemia (FH) are limited. We aimed to explore sex differences in outcomes of AMI among patients with FH from a national administrative dataset. RESEARCH DESIGN AND METHODS: We utilized the National Inpatient Sample to identify admissions with a primary diagnosis of AMI and a secondary diagnosis of FH. Our primary outcome of interest was in-hospital mortality; secondary outcomes were performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), respiratory complications, use of inotropes, use of mechanical circulatory support (MCS), bleeding complications, transfusion and facility discharge. We adjusted for demographics (model A), comorbidities (model B), and intervention (model C). RESULTS: Between October 2016 and December 2020, 5,714,993 admissions with a primary diagnosis of AMI were identified, of which 3,035 (0.05%) had a secondary diagnosis of FH. In-hospital mortality did not differ between men and women (Model C, adjusted OR = 0.85; 95% CI 0.28-2.60, p = 0.773). There was no sex difference in the secondary outcomes. CONCLUSION: Despite generally being older and having more comorbidities, women with FH fair equally with men with FH in terms of mortality during AMI admission.


Subject(s)
Databases, Factual , Hospital Mortality , Hyperlipoproteinemia Type II , Myocardial Infarction , Percutaneous Coronary Intervention , Humans , Male , Female , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/therapy , Myocardial Infarction/mortality , Myocardial Infarction/therapy , Myocardial Infarction/epidemiology , Middle Aged , Hospital Mortality/trends , Aged , Sex Factors , United States/epidemiology , Percutaneous Coronary Intervention/methods , Percutaneous Coronary Intervention/statistics & numerical data , Coronary Artery Bypass , Adult , Aged, 80 and over , Hospitalization/statistics & numerical data
8.
Diabetes Obes Metab ; 26(6): 2209-2228, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38505997

ABSTRACT

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.


Subject(s)
Blood Pressure , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Hypoglycemic Agents , Humans , Glucagon-Like Peptide-1 Receptor/agonists , Blood Pressure/drug effects , Hypoglycemic Agents/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/blood , Randomized Controlled Trials as Topic , Liraglutide/therapeutic use , Glucagon-Like Peptides/therapeutic use , Glucagon-Like Peptides/analogs & derivatives , Exenatide/therapeutic use , Exenatide/pharmacology , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Glucagon-Like Peptide-1 Receptor Agonists
9.
Science ; 383(6681): 384-387, 2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38271496

ABSTRACT

Collective couplings of atomic dipoles to a shared electromagnetic environment produce a wide range of many-body phenomena. We report on the direct observation of resonant electric dipole-dipole interactions in a cubic array of atoms in the many-excitation limit. The interactions produce spatially dependent cooperative Lamb shifts when spectroscopically interrogating the millihertz-wide optical clock transition in strontium-87. We show that the ensemble-averaged shifts can be suppressed below the level of evaluated systematic uncertainties for optical atomic clocks. Additionally, we demonstrate that excitation of the atomic dipoles near a Bragg angle can enhance these effects by nearly an order of magnitude compared with nonresonant geometries. Our work demonstrates a platform for precise studies of the quantum many-body physics of spins with long-range interactions mediated by propagating photons.

10.
Am J Hosp Palliat Care ; 41(1): 87-98, 2024 Jan.
Article in English | MEDLINE | ID: mdl-36705612

ABSTRACT

Heart failure (HF) is a chronic, debilitating condition associated with significant morbidity, mortality, and socioeconomic burden. Patients with end-stage HF (ESHF) who are not a candidate for advanced therapies will continue to progress despite standard medical therapy. Thus, the focus of care shifts from prolonging life to controlling symptoms and improving quality of life through palliative care (PC). Because the condition and prognosis of HF patients evolve and can rapidly deteriorate, it is imperative to begin the discussion on end-of-life (EOL) issues early during HF management. These include the completion of an advance directive, do-not-resuscitate orders, and policies on device therapy and discontinuation as part of advance care planning (ACP). ESHF patients who do not have indications for advanced therapies or those who wish not to have a left ventricular assist device (LVAD) or heart transplant (HT) often experience high symptom burden despite adequate medical management. The proper identification and assessment of symptoms such as pain, dyspnea, nausea, depression, and anxiety are essential to the management of ESHF and may be underdiagnosed and undertreated. Psychological support and spiritual care are also crucial to improving the quality of life during EOL. Caregivers of ESHF patients must also be provided supportive care to prevent compassion fatigue and improve resilience in patient care. In this narrative review, we compare the international guidelines and provide an overview of end-of-life and palliative care for patients with ESHF.


Subject(s)
Heart Failure , Terminal Care , Humans , Quality of Life , Palliative Care , Heart Failure/therapy , Death
11.
Expert Rev Cardiovasc Ther ; 21(9): 631-641, 2023.
Article in English | MEDLINE | ID: mdl-37608465

ABSTRACT

BACKGROUND: There is limited evidence on the effect of sex on permanent pacemaker implantation (PPMI) after transcatheter aortic valve replacement (TAVR). The primary objective of this meta-analysis was to determine the role of sex among patients requiring PPMI post-TAVR. METHODS: A literature search was conducted using the SCOPUS, MEDLINE, and CINAHL databases for studies published until October 2022. Eligible studies included published randomized controlled trials (RCTs) and Observational Cohort Studies (OCS) articles that reported PPMI as an outcome of pacemaker status following TAVR. This study was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Publication bias was estimated using a Funnel plot and Egger's test. Data were pooled using a random-effects model. The primary endpoint was the sex difference in PPMI after TAVR, with odds ratios and 95% confidence intervals (CIs) extracted. RESULTS: Data was obtained from 63 studies, and a total of 79,655 patients were included. The cumulative PPMI rate was 15.5% (95% CI, 13.6%-17.7%). The pooled analysis revealed that while there were more females than males undergoing TAVR (51.6%, 95% CI 50.4%-52.8%), males have a 14.5% higher risk for post-TAVR PPMI than females (OR 1.145, 95% CI 1.047-1.253, P < 0.01). CONCLUSIONS: Males are more likely to experience PPMI after TAVR than females. Further research needs to be done to better explain these observed differences in outcomes.


Subject(s)
Aortic Valve Stenosis , Pacemaker, Artificial , Transcatheter Aortic Valve Replacement , Male , Female , Humans , Transcatheter Aortic Valve Replacement/adverse effects , Aortic Valve/surgery , Aortic Valve Stenosis/surgery , Sex Characteristics , Risk Factors , Treatment Outcome
12.
Acad Radiol ; 30(11): 2533-2540, 2023 Nov.
Article in English | MEDLINE | ID: mdl-36925336

ABSTRACT

RATIONALE AND OBJECTIVES: To compare short-term outcomes of CT-guided percutaneous pericardial drainage (PPD) versus subxiphoid surgical pericardial window (PW) drainage and analyze the risk factors associated with their outcomes. MATERIALS AND METHODS: A retrospective chart review of patients who underwent either percutaneous drainage with drainage catheter placement or PW with surgical drain placement for symptomatic pericardial effusion between January 1, 2006 and August 31, 2016 was performed after institutional review board approval (decision number 16-783). The primary objective was to test for associations between the short-term (≤30 days post procedure) complication and recurrence rates in patients with symptomatic pericardial effusions. The secondary objectives were to test for associations between short-term complications with changes in vital signs. RESULTS: Of the 257 procedures included in the final analysis, 142 were in the percutaneous drainage group. Short-term complication rate was significantly greater (p < 0.001) in patients undergoing PW, 17% (19/114), as compared with PPD, 2% (3/142). The estimated odds of having complications in the PW cohort was 9 times greater than the percutaneous drainage cohort (OR = 9.3, 95% CI:  2.7-32.3). No significant difference was observed between whether or not a patient experienced a short-term recurrence and any of the explanatory variables (patient demographics, imaging, and vital signs). CONCLUSION: CT-guided PPD is a safer alternative to surgical PW as it leads to fewer complications without a significant difference in recurrence rate of pericardial effusion.

13.
Phys Rev Lett ; 129(23): 230602, 2022 Dec 02.
Article in English | MEDLINE | ID: mdl-36563207

ABSTRACT

Although the Bethe ansatz solution of the spin-1/2 Heisenberg model dates back nearly a century, the anomalous nature of its high-temperature transport dynamics has only recently been uncovered. Indeed, numerical and experimental observations have demonstrated that spin transport in this paradigmatic model falls into the Kardar-Parisi-Zhang (KPZ) universality class. This has inspired the significantly stronger conjecture that KPZ dynamics, in fact, occur in all integrable spin chains with non-Abelian symmetry. Here, we provide extensive numerical evidence affirming this conjecture. Moreover, we observe that KPZ transport is even more generic, arising in both supersymmetric and periodically driven models. Motivated by recent advances in the realization of SU(N)-symmetric spin models in alkaline-earth-based optical lattice experiments, we propose and analyze a protocol to directly investigate the KPZ scaling function in such systems.

14.
Front Oncol ; 12: 913656, 2022.
Article in English | MEDLINE | ID: mdl-36106109

ABSTRACT

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.

16.
Front Oncol ; 12: 869078, 2022.
Article in English | MEDLINE | ID: mdl-35692755

ABSTRACT

Imprime PGG (Imprime) is in late-stage clinical development as a combinatorial agent with several therapeutic modalities. Here we present pre-clinical mechanistic data supportive of Imprime, a soluble yeast ß-1,3/1,6-glucan pathogen-associated molecular pattern able to prime innate immune cells in a Dectin-1dependent manner. In tumor-free mice, Imprime evoked broad innate immune responses (type I interferon signature, mobilization of myeloid cells, dendritic cell and monocyte/macrophage expression of co-stimulatory ligands like CD86, and activation of natural killer cells). Imprime-mediated activation of myeloid cells also resulted in functional priming of antigen-specific CD8 T cell response. In tumor-bearing mice, Imprime monotherapy further resulted in activation of systemic and tumor infiltrating macrophages and enhanced cytotoxic CD8 T cell trafficking. Imprime enhanced the anti-tumor activity of several combinatorial agents in mouse cancer models; anti-tyrosinase-related protein 1 antibody in B16F10 melanoma experimental lung metastasis model, anti-vascular endothelial growth factor receptor 2 antibody in H1299 and H441 lung cancer, and anti-programmed cell death protein 1 antibody in MC38 colon cancer models. Mechanistically, combining Imprime with these combinatorial therapeutic agents elicited enhanced innate immune activation, supporting immunological synergy. Finally, Imprime treatment induced similar in vitro phenotypic and functional activation of human innate immune cells. Collectively, these data demonstrate Imprime's potential to orchestrate a broad, yet coordinated, anti-cancer immune response and complement existing cancer immunotherapies.

17.
Phys Rev Lett ; 128(9): 093001, 2022 Mar 04.
Article in English | MEDLINE | ID: mdl-35302810

ABSTRACT

The observation of Pauli blocking of atomic spontaneous decay via direct measurements of the atomic population requires the use of long-lived atomic gases where quantum statistics, atom recoil, and cooperative radiative processes are all relevant. We develop a theoretical framework capable of simultaneously accounting for all these effects in the many-body quantum degenerate regime. We apply it to atoms in a single 2D pancake or arrays of pancakes featuring an effective Λ level structure (one excited and two degenerate ground states). We identify a parameter window in which a factor of 2 extension in the atomic lifetime clearly attributable to Pauli blocking should be experimentally observable in deeply degenerate gases with ∼10^{3} atoms. We experimentally observe a suppressed excited-state decay rate, fully consistent with the theory prediction of an enhanced excited-state lifetime, on the ^{1}S_{0}-^{3}P_{1} transition in ^{87}Sr atoms.

18.
Front Psychiatry ; 13: 823504, 2022.
Article in English | MEDLINE | ID: mdl-35211044

ABSTRACT

BACKGROUND: The stigma of internet surfing is a relatively new area of study arising from the popularity of the internet. The Questionnaire on the Internal Stigma of Internet Surfing-9 (QISIS-9) was developed for the Chinese culture, so its suitability for use in other cultural contexts is uncertain. This paper examines the measurement invariance of the QISIS-9 among Sino-Australian undergraduates to verify the cross-cultural measurement invariance of QISIS-9 and promote cross-cultural (nationality) research regarding the internal stigma of internet surfing. METHODS: The Internal Stigma of Internet Surfing-9 (QISIS-9) was used to assess 200 Chinese undergraduates (50% female, Mage = 19.78) and 204 Australian undergraduates (76% female, Mage = 21.10), respectively. RESULTS: A confirmatory factor analysis (CFA) indicated that the single-factor model of QISIS-9 is acceptable with both Chinese and Australian undergraduates. However, the factor loading of Item 9, to which a reverse score is assigned, is not ideal for both samples. Thus, the item should be deleted. According to a multigroup confirmatory factor analysis (MCFA), QISIS-8, the revised version of QISIS-9, meets the strict measurement invariance among the Chinese and Australian participants. The QISIS-8 demonstrated appropriate internal consistency in the scores for both the Chinese and Australian undergraduates. CONCLUSION: The new QISIS-8 can effectively assess the internal stigma of internet surfing among Chinese and Australian undergraduates, and it provides a frame of reference for further cross-cultural (border) comparisons.

19.
Int J Sports Physiol Perform ; 17(4): 549-555, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35008040

ABSTRACT

PURPOSE: To determine (1) the effect of a 40-minute steady-state run on muscle membrane integrity of elite athletes as reflected by serum creatine kinase (CK), (2) whether antioxidant supplementation (AS) with vitamins E and C has a protective effect, and (3) if a minimal blood concentration of vitamin E or C is required for any such protection. METHODS: Fifteen elite-level endurance athletes (V˙O2max=71.5±1.2 mL·kg-1 min-1) were randomly assigned to 6 weeks AS (1000 IU·d-1 natural vitamin E and 1000 mg·d-1 vitamin C) or placebo. Using a double-blind crossover design and 4-week washout period, each treatment was followed by a 40-minute steady-state run at 3 mM blood lactate. Blood samples before and 0 and 24 hours after the run were assayed for serum and red cell α-tocopherol (α-TOH), serum ascorbate, and CK. RESULTS: The AS produced a 2.5-fold, well-correlated (r = .84) increase in serum and red cell α-TOH (P < .001) that attenuated the increase in postrun CK (P = .01). There was no change in serum ascorbate with AS and no relationship with CK (P > .1). Curvilinear regression revealed some evidence that a critical level of serum α-TOH in the vicinity of 12 mg·L-1 was required to attenuate CK efflux, a level only achieved with AS. CONCLUSION: The muscle membrane integrity of elite-level athletes is compromised even during steady-state running of moderate intensity and duration. The AS provided a protective effect, with evidence that a serum α-TOH concentration of around 12 mg·L-1 is required.


Subject(s)
Antioxidants , Muscle, Skeletal , Ascorbic Acid/metabolism , Ascorbic Acid/pharmacology , Athletes , Dietary Supplements , Humans , Muscle, Skeletal/physiology , Vitamin E/pharmacology
20.
J Behav Health Serv Res ; 49(3): 282-298, 2022 07.
Article in English | MEDLINE | ID: mdl-35083657

ABSTRACT

Transitioning from military service is stressful for veterans with service-connected disabilities seeking civilian employment. This descriptive study examined self-assessed mental health, well-being, and substance use of men and women shortly before or after transition from US military service, compared to norms from community and military samples. As part of a prospective study evaluating an innovative employment program, researchers interviewed 229 current and former service members with service-connected disabilities transitioning from U.S. military service. Compared to published norms, respondents reported significantly poorer outcomes on 5 of 6 standardized measures, indicating less life satisfaction, poorer mental health, more symptoms of depression and posttraumatic stress disorder, and greater financial distress. In the previous year, 42% were prescribed opioid medications, over twice the annual opioid prescription rate of 19% in the general US population. Systematic strategies are needed to ensure access for transitioning veterans with serious behavioral health issues to appropriate evidence-based practices.


Subject(s)
Military Personnel , Stress Disorders, Post-Traumatic , Veterans , Analgesics, Opioid , Female , Humans , Male , Mental Health , Military Personnel/psychology , Prospective Studies , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/psychology , Stress Disorders, Post-Traumatic/therapy , United States , Veterans/psychology
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