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Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
JMIR Public Health and Surveillance Jun 2024The COVID-19 pandemic has profoundly affected out-of-hospital cardiac arrest (OHCA) and disrupted the chain of survival. Even after the end of the pandemic, the risk of... (Observational Study)
Observational Study
BACKGROUND
The COVID-19 pandemic has profoundly affected out-of-hospital cardiac arrest (OHCA) and disrupted the chain of survival. Even after the end of the pandemic, the risk of new variants and surges persists. Analyzing the characteristics of OHCA during the pandemic is important to prepare for the next pandemic and to avoid repeated negative outcomes. However, previous studies have yielded somewhat varied results, depending on the health care system or the specific characteristics of social structures.
OBJECTIVE
We aimed to investigate and compare the incidence, outcomes, and characteristics of OHCA during the prepandemic and pandemic periods using data from a nationwide multicenter OHCA registry.
METHODS
We conducted a multicenter, retrospective, observational study using data from the Korean Cardiac Arrest Resuscitation Consortium (KoCARC) registry. This study included adult patients with OHCA in South Korea across 3 distinct 1-year periods: the prepandemic period (from January to December 2019), early phase pandemic period (from July 2020 to June 2021), and late phase pandemic period (from July 2021 to June 2022). We extracted and contrasted the characteristics of patients with OHCA, prehospital time factors, and outcomes for the patients across these 3 periods. The primary outcomes were survival to hospital admission and survival to hospital discharge. The secondary outcome was good neurological outcome.
RESULTS
From the 3 designated periods, a total of 9031 adult patients with OHCA were eligible for analysis (prepandemic: n=2728; early pandemic: n=2954; and late pandemic: n=3349). Witnessed arrest (P<.001) and arrest at home or residence (P=.001) were significantly more frequent during the pandemic period than during the prepandemic period, and automated external defibrillator use by bystanders was lower in the early phase of the pandemic than during other periods. As the pandemic advanced, the rates of the first monitored shockable rhythm (P=.10) and prehospital endotracheal intubation (P<.001) decreased significantly. Time from cardiac arrest cognition to emergency department arrival increased sequentially (prepandemic: 33 min; early pandemic: 35 min; and late pandemic: 36 min; P<.001). Both survival and neurological outcomes worsened as the pandemic progressed, with survival to discharge showing the largest statistical difference (prepandemic: 385/2728, 14.1%; early pandemic: 355/2954, 12%; and late pandemic: 392/3349, 11.7%; P=.01). Additionally, none of the outcomes differed significantly between the early and late phase pandemic periods (all P>.05).
CONCLUSIONS
During the pandemic, especially amid community COVID-19 surges, the incidence of OHCA increased while survival rates and good neurological outcome at discharge decreased. Prehospital OHCA factors, which are directly related to OHCA prognosis, were adversely affected by the pandemic. Ongoing discussions are needed to maintain the chain of survival in the event of a new pandemic.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03222999; https://classic.clinicaltrials.gov/ct2/show/NCT03222999.
Topics: Humans; Out-of-Hospital Cardiac Arrest; Republic of Korea; COVID-19; Registries; Female; Male; Aged; Middle Aged; Incidence; Retrospective Studies; Aged, 80 and over; Pandemics; Cardiopulmonary Resuscitation
PubMed: 38913998
DOI: 10.2196/52402 -
Journal of Medical Internet Research Jun 2024Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for...
BACKGROUND
Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for the assessment and prediction of disease progression. Our study proposes a novel methodology, the Multimorbidity-Adjusted Disability Score (MADS), which integrates disease trajectory methodologies with advanced techniques for assessing interdependencies among concurrent diseases. This approach is designed to better assess the clinical burden of clusters of interrelated diseases and enhance our ability to anticipate disease progression, thereby potentially informing targeted preventive care interventions.
OBJECTIVE
This study aims to evaluate the effectiveness of the MADS in stratifying patients into clinically relevant risk groups based on their multimorbidity profiles, which accurately reflect their clinical complexity and the probabilities of developing new associated disease conditions.
METHODS
In a retrospective multicentric cohort study, we developed the MADS by analyzing disease trajectories and applying Bayesian statistics to determine disease-disease probabilities combined with well-established disability weights. We used major depressive disorder (MDD) as a primary case study for this evaluation. We stratified patients into different risk levels corresponding to different percentiles of MADS distribution. We statistically assessed the association of MADS risk strata with mortality, health care resource use, and disease progression across 1 million individuals from Spain, the United Kingdom, and Finland.
RESULTS
The results revealed significantly different distributions of the assessed outcomes across the MADS risk tiers, including mortality rates; primary care visits; specialized care outpatient consultations; visits in mental health specialized centers; emergency room visits; hospitalizations; pharmacological and nonpharmacological expenditures; and dispensation of antipsychotics, anxiolytics, sedatives, and antidepressants (P<.001 in all cases). Moreover, the results of the pairwise comparisons between adjacent risk tiers illustrate a substantial and gradual pattern of increased mortality rate, heightened health care use, increased health care expenditures, and a raised pharmacological burden as individuals progress from lower MADS risk tiers to higher-risk tiers. The analysis also revealed an augmented risk of multimorbidity progression within the high-risk groups, aligned with a higher incidence of new onsets of MDD-related diseases.
CONCLUSIONS
The MADS seems to be a promising approach for predicting health risks associated with multimorbidity. It might complement current risk assessment state-of-the-art tools by providing valuable insights for tailored epidemiological impact analyses of clusters of interrelated diseases and by accurately assessing multimorbidity progression risks. This study paves the way for innovative digital developments to support advanced health risk assessment strategies. Further validation is required to generalize its use beyond the initial case study of MDD.
Topics: Humans; Retrospective Studies; Multimorbidity; Female; Male; Middle Aged; Risk Assessment; Adult; Aged; Spain; Depressive Disorder, Major; Bayes Theorem; Disease Progression; United Kingdom; Depression; Finland
PubMed: 38913991
DOI: 10.2196/53162 -
Interdisciplinary Cardiovascular and... Jun 2024Diameter-based risk stratification for elective repair of ascending aortic aneurysm fails to prevent type A dissection in many patients. Aneurysm wall stresses may...
OBJECTIVES
Diameter-based risk stratification for elective repair of ascending aortic aneurysm fails to prevent type A dissection in many patients. Aneurysm wall stresses may contribute to risk prediction; however, rates of wall stress change over time are poorly understood. Our objective was to examine aneurysm wall stress changes over three to five years and subsequent all-cause mortality.
METHODS
Male veterans with <5.5-cm ascending aortic aneurysms and computed tomography at baseline and 3 to 5-years follow-up underwent three-dimensional aneurysm model construction. Peak circumferential and longitudinal wall stresses at systole were calculated using finite element analysis. Temporal trends were assessed by mixed-effects modelling. Changes in aortic wall stresses, diameter, and length over time were evaluated as predictors of subsequent 3-year all-cause mortality by Cox proportional hazards modelling.
RESULTS
Sixty-two male veterans were included in the study. Yearly changes in geometric and biomechanical measures were 0.12 mm/yr (95% CI, 0.04-0.20) for aortic diameter, 0.41 mm/yr (0.12-0.71) for aortic length, 1.19 kPa/yr (-5.94-8.33) for peak circumferential stress, and 0.48 kPa/yr (-3.89-4.84) for peak longitudinal stress. Yearly change in peak circumferential stress was significantly associated with hazard of death-hazard ratio for peak circumferential stress growth per 10 kPa/yr, 1.27 (95% CI, 1.02-1.60; p = 0.037); hazard ratio for peak circumferential stress growth ≥ 32 kPa/yr, 8.47 (95% CI, 2.42-30; p < 0.001).
CONCLUSIONS
In this population of nonsurgical aneurysm patients, large temporal changes in peak circumferential stress, but not aortic diameter or length, was associated with all-cause mortality. Biomechanical stress and stress changes over time may be beneficial as additional risk factors for elective surgery in small aneurysms.
PubMed: 38913870
DOI: 10.1093/icvts/ivae116 -
PLoS Pathogens Jun 2024COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly...
COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as ~ 3 and ~ 0.5 TCID50 of SARS-CoV-2, respectively. Mice infected with 105 TCID50 of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and inflammatory mediators could be detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio (NLR). Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy. SARS-CoV-2 could induce the release of circulating neutrophil extracellular traps (NETs), along with activated platelet/endothelium marker. Immunohistochemical staining with anti-platelet factor-4 (PF4) antibody revealed profound platelet aggregates especially within blocked veins of the lungs. We showed that acute SARS-CoV-2 infection triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis. Finally, we highlighted the potential role of Annexin A2 (ANXA2) in fibrinolytic failure. ANXA2 is a calcium-dependent phospholipid-binding protein that forms a heterotertrameric complexes localized at the extracellular membranes with two S100A10 small molecules acting as a co-receptor for tissue-plasminogen activator (t-PA), tightly involved in cell surface fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated de novo ANXA2/S100A10 synthesis, and reduced ANXA2/S100A10 association in infected mice, this protein might serve as druggable targets for development of antithrombotic and/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19.
PubMed: 38913740
DOI: 10.1371/journal.ppat.1011777 -
PloS One 2024Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and disability within this patient demographic. Presently, numerous studies have been conducted to investigate the underlying causes of stroke in individuals with T2DM, yet the findings exhibit inconsistencies.
OBJECTIVE
This paper aims to consolidate and summarize the available evidence concerning the influential factors contributing to stroke among patients diagnosed with T2DM.
METHODS
We conducted a comprehensive search across multiple databases, including Cochrane Library, PubMed, Web Of Science, Embase, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Weipu up to August 2023. Google Scholar was also searched to retrieve gray literature. We calculated odds ratios (OR) and 95% confidence intervals (CI) using Stata software.
RESULTS
Our analysis encompassed 43 observational studies, exploring factors across sociodemographic, biochemical, complications, and hypoglycemic agent categories. The findings identified several risk factors for stroke in patients with T2DM: age, gender, T2DM duration, hypertension, body-mass index (BMI), smoking, Glycated hemoglobin (HbA1c), estimated Glomerular Filtration Rate (eGFR), albuminuria, Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), Coronary heart disease (CHD), Atrial fibrillation (AF), diabetic retinopathy (DR), Peripheral vascular disease (PVD), and carotid plaque. Conversely, exercise, High density lipoprotein cholesterol (HDL-C), metformin (MET), pioglitazone, and metformin combination therapy emerged as protective factors.
CONCLUSION
This study underscores the multitude of influencing factors contributing to stroke in people with T2DM patients, among which the microvascular complications of T2DM play an most important role. Therefore, we emphasize the importance of screening for microvascular complications in patients with T2DM. However, due to limitations arising from the number of articles reviewed, there remain areas where clarity is lacking. Further research efforts are warranted to expand upon and reinforce our current findings.
Topics: Diabetes Mellitus, Type 2; Humans; Stroke; Risk Factors; Hypoglycemic Agents; Glycated Hemoglobin
PubMed: 38913694
DOI: 10.1371/journal.pone.0305954 -
PloS One 2024Environmental factors resulting from climate change and air pollution are risk factors for many chronic conditions including dementia. Although research has shown the... (Review)
Review
Environmental factors resulting from climate change and air pollution are risk factors for many chronic conditions including dementia. Although research has shown the impacts of air pollution in terms of cognitive status, less is known about the association between climate change and specific health-related outcomes of older people living with dementia. In response, we outline a scoping review protocol to systematically review the published literature regarding the evidence of climate change, including temperature and weather variability, on health-related quality of life, morbidity, mobility, falls, the utilization of health resources, and mortality among older adults living with dementia. This scoping review will be guided by the framework proposed by Arksey and O'Malley. Electronic search (Medline, Embase, PsycINFO, CINAHL, Scopus, Web of Science) using relevant subject headings and synonyms for two concepts (older people with dementia, weather/ climate change). No publication date or other restrictions will be applied to the search strategy. No language restriction will be applied in order to understand the impact of non-English studies in the literature. Eligible studies must include older adults (65+years) with dementia living in the community and investigate the impacts of climate change and/or weather on their health-related quality of life, morbidity, mobility, falls, use of health resources and mortality. Two independent reviewers will screen abstracts and select those for a full-text review, perform these reviews, select articles for retention, and extract data from them in a standardized manner. This data will then be synthesized and interpreted. OSF registration: DOI: 10.17605/OSF.IO/YRFM8.
Topics: Humans; Climate Change; Dementia; Weather; Quality of Life; Aged; Accidental Falls
PubMed: 38913693
DOI: 10.1371/journal.pone.0304181 -
PloS One 2024Exploration of interspecies interactions between microorganisms can have taxonomic, ecological, evolutionary, or medical applications. To better explore interactions...
Exploration of interspecies interactions between microorganisms can have taxonomic, ecological, evolutionary, or medical applications. To better explore interactions between microorganisms it is important to establish the ideal conditions that ensure survival of all species involved. In this study, we sought to identify the ideal biotic and abiotic factors that would result in high co-culture viability of two interkingdom species, Pseudomonas aeruginosa and Acanthamoeba castellanii, two soil dwelling microbes. There have been limited studies showing long-term interactions between these two organisms as co-culture can result in high mortality for one or both organisms suggesting a predator-predator interaction may exist between them. In this study, we identified biotic and abiotic conditions that resulted in a high viability for both organisms in long-term co-culture, including optimizing temperature, nutrient concentration, choice of bacterial strains, and the initial ratio of interacting partners. These two species represent ideal partners for studying microbial interactions because amoebae act similarly to mammalian immune cells in many respects, and this can allow researchers to study host-pathogen interactions in vitro. Therefore, long-term interaction studies between these microbes might reveal the evolutionary steps that occur in bacteria when subjected to intense predation, like what occurs when pathogens enter the human body. The culture conditions characterized here resulted in high viability for both organisms for at least 14-days in co-culture suggesting that long-term experimental studies between these species can be achieved using these culture conditions.
Topics: Acanthamoeba castellanii; Pseudomonas aeruginosa; Coculture Techniques; Microbial Interactions; Temperature; Soil Microbiology
PubMed: 38913685
DOI: 10.1371/journal.pone.0305973 -
PloS One 2024The well-established inverse relationship between socioeconomic status (SES) and risk of developing coronary heart disease (CHD) cannot be explained solely by...
BACKGROUND
The well-established inverse relationship between socioeconomic status (SES) and risk of developing coronary heart disease (CHD) cannot be explained solely by differences in traditional risk factors.
OBJECTIVE
To model the role SES plays in the burden of premature CHD in Argentina.
MATERIALS AND METHODS
We used the Cardiovascular Disease Policy Model-Argentina to project incident CHD events and mortality in low and high-SES Argentinean adults 35 to 64 years of age from 2015 to 2024. Using data from the 2018 National Risk Factor Survey, we defined low SES as not finishing high-school and/or reporting a household income in quintiles 1 or 2. We designed simulations to apportion CHD outcomes in low SES adults to: (1) differences in the prevalence of traditional risk factors between low and high SES adults; (2) nontraditional risk associated with low SES status; (3) preventable events if risk factors were improved to ideal levels; and (4) underlying age- and sex-based risk.
RESULTS
56% of Argentina´s 35- to 64-year-old population has low SES. Both high and low SES groups have poor control of traditional risk factors. Compared with high SES population, low SES population had nearly 2-fold higher rates of incident CHD and CHD deaths per 10 000 person-years (incident CHD: men 80.8 [95%CI 76.6-84.9] vs 42.9 [95%CI 37.4-48.1], women 39.0 [95%CI 36.-41.2] vs 18.6 [95%CI 16.3-20.9]; CHD deaths: men 10.0 [95%CI 9.5-10.5] vs 6.0 [95%CI 5.6-6.4], women 3.2 [95%CI 3.0-3.4] vs 1.8 [95%CI 1.7-1.9]). Nontraditional low SES risk accounts for 73.5% and 70.4% of the event rate gap between SES levels for incident CHD and CHD mortality rates, respectively.
DISCUSSION
CHD prevention policies in Argentina should address contextual aspects linked to SES, such as access to education or healthcare, and should also aim to implement known clinical strategies to achieve better control of CHD risk factors in all socioeconomic levels.
Topics: Humans; Argentina; Adult; Middle Aged; Male; Female; Coronary Disease; Social Class; Risk Factors; Prevalence; Low Socioeconomic Status
PubMed: 38913678
DOI: 10.1371/journal.pone.0305948 -
PloS One 2024HIV/AIDS is a chronic disease that challenges public health worldwide and causes morbidity and mortality in humans. The main purpose of this study was to investigate the...
Determinants of longitudinal changes of CD4 cell count and survival time to death of HIV/AIDS patients treated at Yabelo General Hospital, the case of pastoralist area: Using joint modelling approach.
INTRODUCTION
HIV/AIDS is a chronic disease that challenges public health worldwide and causes morbidity and mortality in humans. The main purpose of this study was to investigate the determinants of longitudinal changes in CD4 cell count and survival time to death among HIV/AIDS patients as adults from January 2016 to December 2019 at Yabelo General Hospital. The intellectual gap in this study was focused on the study area, which means that the study related to joint modeling doesn't exist in the pastoralist community of Borena.
METHODS
This study involved 293 adult HIV-infected adults that could be collected from the recorded patient chart data, and the study design is a retrospective cohort design. The study used a Cox proportional hazard model, a linear mixed effect model, and a joint model, which is the combination of both model processes.
RESULTS
The joint model showed that longitudinal CD4 cell count is significantly associated with survival time (p-value = 0.0253). Covariates such as visiting time, age, weight, educational status, ART adherence, and functional status were statistically significant factors associated with mean changes in the CD4 cell count of HIV patients. WHO stage, educational status, place of residence, TB, family history, and opportunistic infection disease had a significant effect on the survival time of HIV patients.
CONCLUSIONS
The estimated association parameter is a negative value, which indicates both outcomes are negatively associated, and higher values of the CD4 cell count are associated with better survival.
Topics: Humans; Male; CD4 Lymphocyte Count; Female; Adult; HIV Infections; Retrospective Studies; Middle Aged; Hospitals, General; Acquired Immunodeficiency Syndrome; Longitudinal Studies; Proportional Hazards Models
PubMed: 38913649
DOI: 10.1371/journal.pone.0305519