Risk Burden Research Articles

Phase 2 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with polycythemia vera (PV).

TPS6595 Background: PV is a myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis that is driven by mutations in JAK2. Currently available treatments reduce thrombotic risk and symptom burden but have little impact on disease course or risk of progression to post-PV myelofibrosis (PPV-MF) or acute myeloid leukemia (AML). There remains a need for novel treatments that can alter the natural history of PV. LSD1 is an enzyme that regulates megakaryocytes and erythrocyte maturation. Bomedemstat is an irreversible inhibitor of LSD1 that has been shown to have manageable safety and clinically relevant activity in other JAK2-mutation–prevalent MPNs (essential thrombocythemia and myelofibrosis). Here, we describe the methods for an open-label phase 2 study (NCT05558696) that has been designed to evaluate the efficacy and safety of bomedemstat in patients with PV who are resistant to or intolerant of standard cytoreductive therapy. Methods: Eligible patients are ≥18 years, have a confirmed diagnosis of PV per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, an ECOG performance status of 0-2, a platelet count of ≥250 × 109/L, an absolute neutrophil count of ≥1.5 × 109/L, and resistance to or intolerance of ≥1 standard cytoreductive therapy. All patients will receive bomedemstat at a starting dose of 40 mg/d by mouth for 36 weeks, with dose titration to a hematocrit target of <45% with no grade ≥1 thrombocytopenia. Treatment with bomedemstat can continue beyond week 36 in patients deriving clinical benefit. Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE version 5.0 criteria and will be monitored for up to 30 days after treatment end. Transfusions or phlebotomy can be administered during treatment as needed. The primary end points are safety and the proportion of patients who achieve a reduction in hematocrit to <45% without phlebotomy by week 36. Secondary end points will be the durability of reduction in hematocrit <45% without phlebotomy; the incidence and durability of reduction in platelet count to ≤450 × 109/L and white blood cell count to <10 × 109/L; the incidence of new thrombotic or major hemorrhagic events; reduction in spleen volume by week 36 in patients with an enlarged spleen at baseline; progression to PPV-MF or myelodysplastic syndrome or transformation to AML; pharmacokinetics; and change in patient-reported symptom burden assessed using the MSAF v4.0 and PGIC. Exploratory end points include change in the concentration of circulating inflammatory cytokines and growth factors, change in mutant allele frequency of JAK2and other mutations, and change in bone marrow fibrosis grade. Approximately 20 patients will be enrolled. Recruitment for this study is currently underway in Australia, the United Kingdom, and the United States. Clinical trial information: NCT05558696 .

Donor genetic burden for cerebrovascular risk and kidney transplant outcome.

Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient. Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes. We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI [1.07, 1.93]) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1year. Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function.

A Comprehensive Excursus of the Roles of Echocardiography in Heart Transplantation Follow-Up.

Current guidelines for the care of heart transplantation recipients recommend routine endomyocardial biopsy and invasive coronary angiography as the cornerstones in the surveillance for acute rejection (AR) and coronary allograft vasculopathy (CAV). Non-invasive tools, including coronary computed tomography angiography and cardiac magnetic resonance, have been introduced into guidelines without roles of their own as gold standards. These techniques also carry the risk of contrast-related kidney injury. There is a need to explore non-invasive approaches providing valuable information while minimizing risks and allowing their application independently of patient comorbidities. Echocardiographic examination can be performed at bedside, serially repeated, and does not carry the burden of contrast-related kidney injury and procedure-related risk. It provides comprehensive assessment of cardiac morphology and function. Advanced echocardiography techniques, including Doppler tissue imaging and strain imaging, may be sensitive tools for the detection of minor myocardial dysfunction, thus providing insight into early detection of AR and CAV. Stress echocardiography may offer a valuable tool in the detection of CAV, while the assessment of coronary flow reserve can unravel coronary microvascular impairment and add prognostic value to conventional stress echocardiography. The review highlights the role of Doppler echocardiography in heart transplantation follow-up, weighting advantages and limitations of the different techniques.

Pulmonary hypertension in the intensive care unit after pediatric allogeneic hematopoietic stem cell transplant: incidence, risk factors, and outcomes.

To determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT). This was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed. Among 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74-3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%). PH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.

The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study

The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors. This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing. 9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0-31·4) from the date of primary cancer diagnosis (4311 [44.9%] were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9-19·5) compared with 0·9% (0·0-2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23-0·29) events per survivor compared with 0·009 (0·000-0·021) events per community control participant. Increasing cumulative burden of grade 1-4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1-6·0; p<0·0001; two conditions: 6·6, 4·6-9·5; p<0·0001; and three conditions: 7·7, 5·1-11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias [RR 1·5, 95% CI 1·2-2·0; p=0·0017]), grade 2 left ventricular systolic dysfunction (2·2, 1·6-3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2-4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1-2 hypertriglyceridaemia, or grade 1-2 vascular stenosis. Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events. The US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Burden of atrial fibrillation risk and outcomes amongst patients attending cardiology and elderly medicine services: prospective in-hospital implementation of the FIND-AF algorithm

Abstract Background Screening for silent AF is becoming increasingly important (1, 2), and the FIND-AF algorithms can use routinely-collected data to identify individuals at higher risk for undiagnosed AF (3). There may be a much higher prevalence of patients at risk for AF and its complications in a hospital environment compared with the community (4). Purpose We prospectively implemented the FIND-AF algorithm within cardiology and geriatric services to quantify the burden of AF risk amongst all-comers, and to understand their outcomes over the next 6 months. Methods We prospectively implemented the FIND-AF algorithm in the cardiology and geriatric departments of three UK hospitals for consecutive inpatient or outpatient attendances from February 1 to July 13th 2023. We assessed the number of individuals attending each service eligible for an AF screening protocol (exclusion criteria: age &amp;lt;30 years, history of AF, on a palliative care pathway, use of oral anticoagulation), and calculated the burden of AF risk in each service. Patients were followed up for 6 months for the primary outcome of incident AF, heart failure (HF), stroke/transient ischaemic attack (TIA)/systemic embolism, and death. Incident diagnoses were the first record of that condition in primary or secondary care records. Rate ratios (RRs) with 95% confidence intervals (CIs) for combined incident cardiovascular outcomes or death were derived through Poisson regression for predicted higher versus lower AF risk. Results Of 467 consecutive patients, 364 were eligible for AF screening. 66 were excluded due to a previous diagnosis of AF, 25 were already prescribed a long-term oral anticoagulant, 5 were on a palliative care pathway and 7 were aged &amp;lt;30 years. Baseline characteristics of each cohort are summarised in Table 1. Of patients eligible for AF screening, those attending geriatrics were at higher risk of incident AF than patients attending cardiology (median FIND-AF score: geriatrics, 0.015, 95% CI 0.008 - 0.024; cardiology, 0.005, 95% CI 0.001-0.015; p&amp;lt;0.05; distributions of risk summarised in Figure 1) and had a higher stroke risk. Absolute risk of AF was greater than 5% within the next 6 months for 11.6% and 9.1% of geriatric and cardiology patients, respectively. Of the eligible cohort, 328 had follow up at 6 months, with 46 experiencing the primary outcome (9, 7, 3, and 27 recorded cases of AF, HF, stroke/TIA, and death, respectively). The higher predicted risk cohort, compared to lower predicted risk, had a higher risk of combined incident AF, heart failure, or stroke/TIA/systemic embolism (Rate ratio: 5.59, 95% CI 1.13-101.01) and death (RR 9.68, 2.06-172.85). Conclusions The FIND-AF algorithm can be prospectively implemented in hospital records to identify cardiology and geriatric patients at risk of incident AF, heart failure, thromboembolic disease and death. There is an opportunity to conduct risk-guided screening in the context of hospital attendances.

ECG risk markers among premenopausal and postmenopausal SCD victims

Abstract Background Majority of the SCD victims aged 50 years or younger are male. On average menopause occurs at the age of 51.4 years and it has a substantial role in cardiovascular risk burden among women. The mechanisms and risk markers of SCD are not as well defined for women as they are for men possible due to difference in population burden, and electrocardiographic risk markers do not seem to make a difference in this matter. Purpose The aim of this study was to determine electrocardiographic findings among women at pre- and postmenopausal age in a large SCD population. Methods The Fingesture study has systematically collected clinical and autopsy data from SCD victims in Northern Finland between 1998 and 2017. The cohort consists of 5,869 SCD victims of which 1,238 are women (21.1%). Antemortem electrocardiograms (ECG) were recorded in 1,101 subjects (women 25.3%). Women aged ≥ 52 years were considered as postmenopausal and ≤ 51 years old as premenopausal as the direct information of the menopause lacked due to the retrospective nature of this autopsy-based data. Results Only 7.9% of the female subjects experienced SCD under age of 52 years (P&amp;lt;0.001). No statistically significant differences in ECG abnormalities were found between pre- and postmenopausal women. However, almost one female SCD victim out of four lacked any ECG abnormalities in premortem ECG (26.3% of premenopausal and 24.2% of postmenopausal women, P=1.000). In general, ECG abnormalities were more prevalent in SCD victims at postmenopausal age. Though, fragmented QRS, particularly in the lateral ECG leads, was observed in 47.4% of women at premenopausal age group and in 42.1% of women at postmenopausal age even though statistical significance was not obtained (p=0.810). ECG-LVH, as per Cornell's criteria, was present in 4.8% of individuals in premenopausal age group whereas in postmenopausal age group, it was observed in 19.0% of subjects (P=0.140). ECG variables are presented in Table 1. When the analysis was repeated between the women &amp;lt;55 years of age and ≥55 years of age, only left ventricular hypertrophy (LVH; Cornell) was statistically significant and more common in women ≥55 years old (19.5% vs. 3.6%, P=0.037). Conclusion Premenopausal SCDs are rare. Approximately one female SCD victim out of four did not have any ECG abnormalities prior to SCD. Only ECG-LVH remained statistically significant in analysis between younger and older women, and was clearly more prevalent finding among postmenopausal SCD victims.Table 1

Clinical characteristics and atrial fibrillation management in hospitalized patients with heart failure with reduced versus preserved ejection fraction

Abstract Funding Acknowledgements None. Background Non-valvular atrial fibrillation (NVAF) and heart failure (HF) frequently coexist. AF management in HF is currently changing with increasing role of rhythm control. Data about clinical characteristics and AF management in hospitalized patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) are lacking. The purpose of the study was to assess the clinical characteristics and AF management in hospitalized patients with NVAF and HFrEF and compare them to those of NVAF and HFpEF. Methods Consecutive NVAF patients hospitalized with HF decompensation between January 2020 and May 2022 were retrospectively evaluated. Patients were divided into two groups: HFrEF and HFpEF (defined as left ventricular ejection fraction &amp;gt; 40%). Clinical characteristics and AF treatment strategy in both groups were studied and compared. Numerical data are expressed as median (interquartile range). P&amp;lt;0.05 was considered significant. Results In a total of 388 AF-HF patients (age 73.5 years [66-82], 59.3% males), 147 (37.9%) had reduced ejection fraction. Patients with HFrEF compared to those with HFpEF were younger (69.3 vs 74.7 years; P &amp;lt; 0.001), more often male and with a higher rate of NYHA classes III-IV (73.9% vs 63.5%; P &amp;lt; 0.05), N-terminal pro-B-type natriuretic peptide level (2658.5 pg/ml vs 1799.1 pg/ml; p&amp;lt;0.001), sum of B-lines by lung ultrasound (35.2 vs 28.9; P&amp;lt;0.05) and prevalence of non-paroxysmal forms of AF (70.4% vs 50.4%; p &amp;lt; 0.05). Patients with HFrEF had a higher burden of coronary artery disease, chronic kidney disease and prior stroke (31.7% vs 19.2%, 83.9% vs 69.0, 18.5% vs 9.7%, respectively; p&amp;lt; 0.05 for all) than HFpEF patients. Patients with HFpEF were more likely than those with HFrEF to have diabetes mellitus (25.9% vs 37.1%; p&amp;lt; 0.05) The subgroup of patients with HFrEF compared to those with HFpEF had higher bleeding risk (HAS-BLED ≥3 in 32.1% vs 20.4%, P&amp;lt;0.05) due to more frequent abnormal renal/liver function, concomitant antithrombotic treatment/alcohol, prior stroke (24.7% vs 10.6%, 28.4% vs 16.8%, 18.5% vs 9.7%, respectively; P&amp;lt;0.05 for all) but lower thromboembolic risk according to CHA 2 DS 2 -VASc (4.0 vs 4.4; p &amp;lt; 0.05). Oral anticoagulants (OAC) were administered in 88% of patients on discharge. Patterns of anticoagulation administration didn’t differ between the two groups. Patients with HFrEF were less likely to receive first-line rhythm control for AF compared to HFpEF patients (36.1% vs 68.1%; p&amp;lt;0.05). Conclusion Hospitalized patients with NVAF and HFrEF compared to those with HFpEF were younger, with greater severity of HF, higher burden of comorbidities and bleeding risk and slightly lower thromboembolic risk. Despite different clinical characteristics, OAC administration patterns were similar and OAC prescription rate was not optimal in both groups. There is a need for improvement of guideline adherence to first-line rhythm control strategy in AF and HFrEF.

Global, regional, and national burden of atrial fibrillation/flutter related to metabolic risks over three decades: estimates from the global burden of disease study 2019.

Atrial fibrillation/atrial flutter (AF/AFL) remains a significant public health concern on a global scale, with metabolic risks playing an increasingly prominent role. This study aimed to investigate comprehensive epidemiological data and trends concerning the metabolic risks related-AF/AFL burden based on the data from the Global Burden of Disease study in 2019. The analysis of disease burden focused on numbers, age-standardized rates of deaths, disability-adjusted life years (DALYs), and estimated annual percentage change, while considering factors of age, sex, sociodemographic index (SDI), and locations. In 2019, there was a culmination of 137 179 deaths and 4 099 146 DALYs caused by metabolic risks related-AF/AFL worldwide, with an increase of 162.95% and 120.30%, respectively from 1990. High and high-middle SDI regions predominantly carried the burden of AF/AFL associated with metabolic risks, while a shift towards lower SDI regions had been occurring. Montenegro had the highest recorded death rate (7.6 per 100 000) and DALYs rate (146.3 per 100 000). An asymmetrically inverted V-shaped correlation was found between SDI and deaths/DALYs rates. Moreover, females and the elderly exhibited higher AF/AFL burdens, and young adults (over 40 years old) also experienced an annual increase. The global AF/AFL burden related to metabolic risks has significantly increased over the past three decades, with considerable spatiotemporal, gender-based, and age-related heterogeneity. These findings shed valuable light on the trends in the burden of metabolic risks related-AF/AFL and offered insights into corresponding strategies.

Impact of Smokeless Tobacco on Cardiovascular Disease Risk in a Nigerian Metropolitan City.

The use of smokeless tobacco products (STP) as a substitute for tobacco smoking is driving increasing consumption of these products especially in developing countries. The study sought to make comparison of cardiovascular risk profile between chronic STP users and suitably matched tobacco-naïve controls. This is a preliminary report from the cross sectional part of a two-arm prospective study of Smokeless Tobacco Products Composition and Exposure Outcome in Enugu metropolis, Nigeria. Consecutively recruited current Smokeless tobacco users, who had no history of cigarette smoking, aged 18years and above, residing in selected communities in Enugu metropolis, Nigeria were recruited for the study from October 2022 to July 2023. Age and sex matched non-tobacco users from same localities as the study subjects served as controls. Written informed consent to participate in the study was obtained from all study participants. All participants were screened by the investigators, using the study case report forms, to obtain data on medical history, demographic, clinical, laboratory, and electrocardiographic evaluation. Data from 54 STP-users and 54 non-STP-users (mean age 56.58 ± 8.15years) were analyzed. Anthropometric parameters were similar in both groups. Smokeless tobacco users had higher erect and supine blood pressure indices as well asgreater postural drop in systolic blood pressure. The occurrence of diabetes mellitus (20.37% versus 5.56%) and hypertension (25.93%; 11.11%) was significantly higher in the STP-users than in the non-user population, (p = 0.02192 and 0.04751 respectively). Electrocardiographic evaluation showed significantly increased QTc and dispersions of P-wave, QRS and QT intervals as well as reduced PR interval in STP users. Electrocardiographic abnormalities observed in STP users include left ventricular hypertrophy, left atrial enlargement, ST-segment elevation, short PR interval and long QTc. Use of smokeless tobacco products is associated with increased risk burden of diabetes mellitus and hypertensive heart disease. Electrocardiographic findings linked to STP-use in this study are features consistent with arrhythmia, ventricular repolarization abnormality, myocardial hypertrophy and ischaemia, suggesting that smokeless tobacco products are not safe substitutes for tobacco smoking.

Contemporary Outcomes of Acute Coronary Syndromes in Indigenous Compared With Non-Indigenous Patients: A Northern Saskatchewan Perspective

BackgroundIn patients presenting with an acute coronary syndrome (ACS), the impact of efforts to bridge historical care gaps between Indigenous and non-Indigenous patients remains limited. MethodsFor consecutive ACS presentations (ST-segment elevation myocardial infarction [STEMI] and non–ST-segment elevation myocardial infarction [NSTEMI]/unstable angina [UA], respectively) at the Royal University Hospital, Saskatoon, we compared self-identified Indigenous and non-Indigenous patients’ demographics, treatments, and all-cause mortality (in-hospital and within 3 years). We used propensity score inverse probability weighting to mitigate confounding and Cox regression models to estimate the adjusted hazard ratio (aHR) for all-cause mortality. ResultsOf 3946 ACS patients, 37.2% (n = 1468) were STEMI, of whom 11.3% (n = 166) were Indigenous. Of the NSTEMI/UA (n = 2478), 12.6% (n = 311), were Indigenous. Overall, Indigenous compared with non-Indigenous patients were likely to be younger, female, have higher risk burden, and live more remotely; Indigenous STEMI patients triaged to primary percutaneous coronary intervention had longer times from first medical contact to device, and Indigenous NSTEMI/UA patients more likely to present with heart failure, cardiac arrest, and cardiogenic shock. No significant differences were noted for in-hospital mortality (STEMI 8.4% vs 5.7% [P = 0.16], NSTEMI/UA 1.9% vs 1.6% [P = 0.68]), although in follow-up, Indigenous STEMI patients were associated with a higher all-cause mortality risk (aHR 1.98, 95% CI 1.19-3.31; P = 0.009) with no between-group differences evident for NSTEMI/UA (aHR 1.03, 95% CI 0.63 1.69; P = 0.91). ConclusionsIndigenous compared with non-Indigenous patients presenting with an ACS had higher cardiovascular risk profiles and consequent residual mortality risk. Improving primary care and intensifying secondary risk reduction, particularly for Indigenous patients, will substantially modify ACS outcomes in Saskatchewan.

Elevated Glucose Levels Increase Oxidative Stress in Human Cerebral Microvascular Endothelial Cells

Although glucose is the primary fuel source for cerebral metabolism and function, chronic exposure to high glucose levels impairs cerebral endothelial cell function and increases the risk of cerebrovascular accidents (CVA). Indeed, hyperglycemia is linked to an increased risk and prevalence of ischemic stroke, primarily attributed to the detrimental impact of glucose on cerebral endothelial cell function. The direct and indirect effects of glucose on brain endothelial cells are complex and not well understood. It is known that hyperglycemia can induce a profound pro-oxidative state with deleterious effects on peripheral vascular function resulting in pathologic outcome. The experimental aim of this study was to determine, in vitro, the effect of elevated glucose concentrations on cerebral endothelial cell oxidative stress. Human cerebral microvascular endothelial cells (hCMECs) were cultured (3rd passage) and incubated with culture media containing 5 mM D-glucose (normal glucose condition [NG]), 6.5 mM glucose (concentration representative of impaired fasting glucose [IFG]), and 8 mM (concentration representative of type 2 diabetes [T2D]) for 3 hours. Cells were harvested and intracellular reactive oxygen species (ROS) production was determined using CellROX Deep Red Reagent and expression of key anti-oxidant defense proteins, superoxide dismutase 1 (SOD-1) and catalase, were determined by capillary electrophoresis immunoassay. In separate experiments, the effect of each glucose condition was determined in the presence of the ROS scavenger, vitamin C (200 μmol). Cells treated with glucose concentration representing IFG (137+8 %) and T2D (162+12%) significantly increased intracellular ROS compared with NG (98+3 %). Concordantly, expression of SOD-1 and catalase were significantly higher in hCMECs treated with glucose concentration representing IFG (190.2+17.8 AU; 134.7+15.4 AU, respectively) and T2D (186.7+19.6 AU; 137.2+17.5 AU, respectively) compared with NG (24.4+1.8 AU; 65.6+4.3 AU, respectively). Pretreatment of cells with vitamin C prevented the increase in ROS in both the IFG and T2D conditions. Of note, there were no significant differences in ROS or the expression of SOD-1 and catalase in hCMECs between the IFG and T2D glucose conditions. In conclusion, glucose concentrations associated with IFG and T2D markedly increased ROS in hCMECs. In addition, there was a compensatory increase in SOD-1 and catalase to counteract the increase in cellular oxidative burden. Similar effects between the IFG and T2D glucose conditions on the oxidative milieu of hCMECs is consistent with the similar clinical cerebrovascular risk burden between these pathologic conditions. Glucose-induced increased oxidative stress in cerebral endothelial cells may contribute to the increased risk of CVA, such as ischemic stroke, associated with IFG and T2D. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neglected cardiometabolic risk factors and subclinical target organ damage in post-menopausal women with normal glucose tolerance.

Menopausal transition is a crucial step in the women's cardiovascular health, and the risk stratification in apparently health post-menopausal females has been rarely assessed. Heart ultrasonography, unusually performed in such subjects, would be able to detect initial signs of organ damage. We described the cardiovascular risk profile of non-diabetic post-menopausal women, evaluating how easily computed, biochemistry-derived scores were related to ultrasonographic measures of target organ damage. We analyzed the characteristics of a cohort of two-hundred and seventy-three women consecutively referring to a prevention program of Azienda Ospedaliero-Universitaria Pisana (years 2017-2022) who underwent clinical evaluation, complete routine biochemical analyses with proxies of insulin resistance, heart and carotid ultrasonography. The cohort was further divided into four groups according to presence of isolated hypercholesterolemia (HC, 37%), isolated hypertension (HT, 5%), both HC/HT (38%), or none of them. In HC and HC/HT, LDL cholesterol was sharply above the recommended values (149 [134-171] mg/dL and 141 [123-159] mg/dL, respectively). E/e' ratio and left atrium size were augmented in HT women and further worsened in HT/HC, with an independent effect of hypertension (E/e' ß=0.055, P=0.013, left atrium volume ß=0.059, P=0.003). Presence of carotid plaques was independently linked to hypertension (ß=0.474, P=0.003). In HC and HC/HT, the Triglycerides-Glucose Index, a surrogate of insulin resistance, was higher than in the other classes (P=0.0013), and it was associated with E/A in HC and HT/HC, with a significative interaction (P=0.0004) with hypertension. Past hormone replacement therapy did not influence clinical, biochemical or echocardiographic parameters. Postmenopausal women display a high cardiovascular risk burden; a simple clinical and biochemistry screening would be advisable to identify and treat those more at risk. Cardiac ultrasonographic parameters were worse in hypertensive, hypercholesterolemic and insulin-resistant subjects, who may also deserve a deep and early instrumental characterization, especially when these conditions are associated.

Global burden of self-harm and interpersonal violence and influencing factors study 1990–2019: analysis of the global burden of disease study

IntroductionWidespread concern exists in today’s world regarding self-harm and interpersonal violence. This study to analyze the changes in temporal trends and spatial patterns of risk factors and burdens of self-harm and interpersonal violence using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.MethodsTemporal trends in self-harm and interpersonal violence were initially summarized using the estimated annual percentage change (EAPC). Data were compiled and visualized to delineate changes in disease burden and factors influencing self-harm and interpersonal violence from 1990 to 2019, stratified by gender, age and GBD region.ResultsIn 2019, the DALY rates of self-harm were 424.7(95% UI 383.25, 466.93). Over the period from 1999 to 2019, self-harm exhibited an overall decreasing trend, with the EAPC of -1.5351 (95% CI -1.6194, -1.4507), -2.0205 (95% CI -2.166, -1.8740) and -2.0605 (95% CI -2.2089, -1.9119), respectively. In contrast, the incidence rate of interpersonal violence was significantly higher than self-harm, with a rate of 413.44 (95% UI 329.88, 502.37) per 100,000 population. Mortality and DALYs of interpersonal violence were lower than those of self-harm, at 5.22 (95% UI 4.87, 5.63) and 342.43 (95% UI 316.61, 371.55). Disease burden of self-harm and interpersonal violence varied by gender, age groups and region. Specific risk factors showed that alcohol use, high temperature and drug use were the main risk factors for self-harm, while alcohol use, intimate partner violence and high temperature were associated with interpersonal violence. Low temperature was a common protective factor for both self-harm and interpersonal violence. The burden of self-harm and interpersonal violence was attributed to different factors influences in different SDI regions.ConclusionsThe study explored temporal trends and spatial distribution of the global disease burden of self-harm and interpersonal violence, emphasizing the significant impact of factors such as alcohol use, temperature, and drug use on disease burden. Further research and policy actions are needed to interpret recent changes of disease burden of self-harm and interpersonal violence, and dedicated efforts should be implemented to devise evidence-based interventions and policies to curtail risk factors and protect high-risk groups.

Oxidative Stress and Antioxidant Status in Adult Patients with Transfusion-Dependent Thalassemia: Correlation with Demographic, Laboratory, and Clinical Biomarkers.

Iron overload in beta transfusion-dependent thalassemia (β-TDT) may provoke oxidative stress and reduction of the antioxidant defenses, with serious consequences for the disease course and complications. The present study evaluated the oxidant/antioxidant status of β-TDT patients and its correlation with demographic, clinical, laboratory, and instrumental biomarkers. The OXY-adsorbent assay and the d-ROMs (Diacron, Grosseto, Italy) were evaluated in 58 β-TDT patients (mean age: 37.55 ± 7.83 years, 28 females) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload was quantified with R2* magnetic resonance imaging. Mean OXY was 323.75 ± 113.19 μmol HClO/mL and 39 (67.2%) patients showed a decreased OXY-Adsorbent level (<350 μmol HClO/mL), of whom 22 (37.9%) showed severely reduced levels. Mean d-ROMs was 305.12 ± 62.19 UA; 12 (20.7%) patients showed oxidative stress, and 4 (6.9%) elevated oxidative stress. OXY showed a significant negative correlation with global and segmental cardiac iron levels. D-ROMs levels significantly correlated with markers of cardiovascular risk (aging, glycemia, and N-terminal pro-B-type natriuretic peptide). Antioxidant depletion is frequent in β-TDT patients, where OXY might serve as additive biomarker to assess heart iron status, whereas the d-ROMs might be helpful to assess the cardiovascular risk burden.

Mutational landscape, inhibitor development, and health-care burden in non-severe haemophilia A: A single-centre Australian experience.

To characterise non-severe haemophilia A (HA) patients enrolled on the Australian Bleeding Disorders Registry (ABDR) treated through a state-wide Haemophilia Treatment Centre (HTC) with respect to their mutational profile, inhibitor risk and health-care burden. We conducted a single-centre observational study of all non-severe HA patients treated at the Alfred Health HTC registered on the ABDR as of the 26thJuly 2023. Data were extracted from the ABDR and electronic medical record (EMR) regarding demographics, severity, genetic testing, treatment, inhibitors, bleeding events and procedures. Inhibitor risk was calculated as a function of exposure days (EDs) of FVIII replacement. There were 289 non-severe HA patients treated at the Alfred HTC registered on the ABDR as of July 2023, all of whom were adult patients aged>18 years old. Genotyping had been performed in 228/289 (78.9%). Of the inhibitor analysis population, 14/193 (7.3%) had an inhibitor. The cumulative incidence of inhibitor development at 75 EDs was 31% (95% CI 13%-46%). The median cost of bypassing agents per inhibitor patient was $57,087.50/year. These results demonstrate a relatively high inhibitor prevalence and incidence risk in non-severe HA compared to previously published work, although this may partly reflect a smaller population size. High rates of genotyping have allowed representative mutational characterisation. The burden of care imposed by non-severe HA in terms of bleeding events, procedures and bypassing agent cost is larger than expected, particularly within the inhibitor population.

Rematriation and climate justice: Intersections of indigenous health and place

Indigenous peoples shoulder a disproportionate burden of risk posed by climate change and associated environmental shifts. Simultaneously, Indigenous communities are recognized as arbiters of planetary health and climate resilience due to their interdependence with local ecosystems, traditional lifeways and Indigenous Traditional Ecological Knowledge(s) (ITEKs) that inform adaptation and mitigation programming. Accordingly, Indigenous Peoples protect and steward 80% of the global biodiversity, while only inhabiting 22% of the earth's surface, and comprising only 5% of the earth's global population [1]. Yet, climate resilience often disregards opportunities for Indigenous communities to explore reparative frameworks that seek to heal the social and ecological determinants responsible for climate-related vulnerabilities associated with histories of colonial subjugation. This manuscript offers critical insights and Indigenous perspectives on climate justice, while redressing the intersection of place-based determinants of Indigenous health, sovereignty and self-determination, with ancestral land-based practices of birthing justice and rematriation of Indigenous territories. As Indigenous communities grapple with land dispossession and confinement - rematriation, ancestral remembrance and reciprocity offer novel insights on the critical relationship to territorial homelands and the sanctity of place to Indigenous health. In closing, the authors explore opportunities for decolonizing relationships to place from climate justice perspectives, while discussing a case of rematriation and healing at Bdóte, the place of genesis for Dakota Peoples, also known as Minneapolis and Saint Paul, MN.

Exploring the impact of ambient temperature on respiratory diseases admissions, length of Stay, and hospitalization costs in Lanzhou City, based on distributed lag non-linear model

This study was to explore the relationships between daily mean temperature and hospital admissions, length of stay and hospitalization costs for respiratory diseases, and to estimate the risk effects and burden of disease. A time-series analysis was conducted by distributed lag non-linear model (DLNM) to explore the exposure-lag-response relationships between daily mean temperature and hospital admissions, length of stay, and hospitalization costs for respiratory diseases. The total cumulative exposure between the daily admissions, length of stay and hospitalization costs of respiratory diseases and the daily mean temperature showed significant nonlinear relationships, all with a shape approximately “W”. Extremely low temperature presented the greatest risk to respiratory diseases of admissions, length of stay and hospitalization costs, with the relative risks of 1.66 (95 % CI:1.32–2.09), 1.71 (95 % CI:1.33–2.20), 2.09 (95 % CI:1.53–2.84), respectively. The risks caused by low temperatures have delayed effect, capable of generating higher risks within lag 21 days. In contrast, the effects of high temperatures on the three outcomes only in the short term. The relative risks of exposure to extremely cold weather for elderly patients were the greatest, which were 2.47 (95 % CI:1.89–3.24), 2.11 (95 % CI:1.58–2.81) and 2.59 (95 % CI:1.81–3.70), respectively. In Lanzhou city, both low and high temperatures posed a certain risk to the hospital admissions, length of stay and hospitalization costs of respiratory diseases. Cold temperature exposure is the main risk factor to increase the risks of the three outcomes, and its risks have significant lag effect. Elderly patients are vulnerable to cold temperature exposure.

Predicting Antibiotic Resistance and Assessing the Risk Burden from Antibiotics: A Holistic Modeling Framework in a Tropical Reservoir.

Predicting the hotspots of antimicrobial resistance (AMR) in aquatics is crucial for managing associated risks. We developed an integrated modeling framework toward predicting the spatiotemporal abundance of antibiotics, indicator bacteria, and their corresponding antibiotic-resistant bacteria (ARB), as well as assessing the potential AMR risks to the aquatic ecosystem in a tropical reservoir. Our focus was on two antibiotics, sulfamethoxazole (SMX) and trimethoprim (TMP), and on Escherichia coli (E. coli) and its variant resistant to sulfamethoxazole-trimethoprim (EC_SXT). We validated the predictive model using withheld data, with all Nash-Sutcliffe efficiency (NSE) values above 0.79, absolute relative difference (ARD) less than 25%, and coefficient of determination (R2) greater than 0.800 for the modeled targets. Predictions indicated concentrations of 1-15 ng/L for SMX, 0.5-5 ng/L for TMP, and 0 to 5 (log10 MPN/100 mL) for E. coli and -1.1 to 3.5 (log10 CFU/100 mL) for EC_SXT. Risk assessment suggested that the predicted TMP could pose a higher risk of AMR development than SMX, but SMX could possess a higher ecological risk. The study lays down a hybrid modeling framework for integrating a statistic model with a process-based model to predict AMR in a holistic manner, thus facilitating the development of a better risk management framework.

Resolution of the Expert Forum "New therapeutic horizons of NAFLD"

Aim. To present the materials of the Expert Forum "New therapeutic horizons of NAFLD," held on December 19, 2023, on the updated nomenclature of fatty liver disease (FLD), its main issues of diagnosis and treatment, the burden of cardiovascular risk in FLD patients. Executive Summary of the Resolution. It is recommended that the latest update of the FLD nomenclature be considered for adaptation to the clinical practice of doctors of all therapeutic specialties. Due to the high prevalence of a combination of non-alcoholic fatty liver disease (NAFLD) and an alcoholic component in the Russian Federation, it is essential to distinguish this subgroup of patients. Numerous clinical conditions associated with NAFLD include cardiovascular disease, pre-diabetes/type 2 diabetes mellitus, polycystic ovary syndrome, obstructive sleep apnea, sarcopenic obesity, cholelithiasis, and chronic kidney disease. Once a diagnosis of NAFLD has been made, further examination of patients should be aimed at detecting the presence of fibrosis using non-invasive methods such as transient liver elastography, FibroTest, and calculation of the FIB-4 fibrosis index. The original ademethionine can be considered a universal drug in treating NAFLD due to reducing oxidative stress and correcting concomitant fatigue and asthenia.