Adverse Clinical Outcomes In Patients Research Articles

The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

The potential of triglyceride-glucose index in improving the prediction of post-percutaneous coronary intervention clinical outcomes: a systematic review and meta-analysis

Introduction Despite percutaneous coronary intervention is the current preferred reperfusion modality, the incidence of major adverse cardiovascular events (MACE) is still high. Currently, GRACE score is used for predicting PCI outcomes. The TyG (triglyceride-glucose) index, a potential predictor based on insulin resistance of cardiovascular disease, has not been considered in the GRACE score. Objective To assess the potential of the TyG index in predicting cardiovascular adverse clinical outcomes in patients undergoing PCI. Method Following PRISMA guidelines, the authors reviewed literature from five databases. We included studies investigating post-PCI outcomes based on the TyG index level. Effect size was estimated using RevMan to calculate pooled odds ratio and mean difference, and R software to perform diagnostic test accuracy. Results Overall, 31,671 post-PCI patients with acute coronary syndrome were included in this study. A significant difference in TyG index was found between patients who experienced MACE and those who did not [MD: 0.3 (0.2–0.4), p < .05]. Higher TyG index was strongly correlated with higher MACE [OR: 2.01 (1.45–2.77), p < .05], especially revascularization [OR: 2.40 (1.72–3.36), p < .05], followed by myocardial infarction [OR: 1.80 (2.41–2.86), p < .05], death [OR: 1.36 (0.86–2.15), p = .19], and stroke [OR: 1.09 (0.79–1.50), p = .59]. Tyg Index showed 55% sensitivity, 60% specificity, and 0.612 accuracy. The addition of the TyG index to the GRACE scoring improved the predictive model’s AUC (0.746 vs. 0.809). Conclusion This systematic review and meta-analysis comprises evidence-based results for the correlation of TyG index and post-PCI outcomes, demonstrating modest sensitivity, specificity, accuracy, and enhanced predictive value of GRACE score.

Dermatological and non-dermatological risk factors associated with adverse clinical outcomes in patients with Staphylococcus aureus bacteraemia

Dermatological and non-dermatological risk factors associated with adverse clinical outcomes in patients with Staphylococcus aureus bacteraemia

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R=-0.30, P<0.001) and fewer daily steps (R=-0.19, P=0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6months were positively related (R=0.25, P=0.004). This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

Predictors of Disease Progression and Adverse Clinical Outcomes in Patients with Moderate Aortic Stenosis Using an Artificial Intelligence-Based Software Platform.

Moderate Aortic Stenosis (AS) patients have a higher risk of adverse clinical outcomes than the general population. How this risk compares to those with severe AS, along with factors associated with outcomes and disease progression, is less clear. We analyzed serial echoes (from 2017-2019) from a single healthcare system using Tempus Next (Chicago, IL) software. AS severity was defined according to American Heart Association/American College of Cardiology (AHA/ACC) guidelines. Outcomes of interest included death or heart failure (HF) hospitalization. We used Cox proportional hazards models and logistic regression to identify predictors of clinical outcome and disease progression, respectively. From 82,805 echoes for 61,546 patients, 1,770; 914; 565; and 1,463 patients had no, mild, moderate, or severe AS, respectively. Both moderate and severe AS patients experienced a similar prevalence of adverse clinical outcomes (p=0.45) that was significantly higher than patients without AS (p<0.01). Among moderate AS patients, atrial fibrillation (AF) (HR=3.29, 95% CI=1.79-6.02, p<0.001) and ESRD (HR=3.34, 95% CI=1.87-5.95, p<0.001) were associated with adverse clinical outcomes. One-third of moderate AS patients with a subsequent echo (139/434) progressed to severe AS within one year. In conclusion, moderate AS patients can progress rapidly to severe AS and experience a similar risk of adverse clinical outcomes; predictors include AF and low LVEF. Machine learning algorithms may help identify these patients. Whether these patients may warrant earlier intervention merits further study.

Hypothermia on the first day of ICU admission leads to increased in-hospital mortality in patients with subarachnoid hemorrhage

The relationship between early spontaneous hypothermia and adverse clinical outcomes in patients with subarachnoid hemorrhage (SAH) has not been paid much attention. We designed this retrospective cohort study to determine this relationship by analyzing the association between the lowest body temperature (T-lowest) on the first day of ICU admission and in-hospital mortality. In this study, 550 participants with non-traumatic SAH were chosen from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Multivariate Cox regression analysis showed that T-lowest was nonlinearity correlated with in-hospital mortality (HR = 0.72, 95% CI: 0.59–0.86, p < 0.001). We divided the T-lowest into quartile groups. In comparison to reference group Q1 (31.30–36.06 ℃), group Q3 (36.56–36.72 ℃) had a 50% lower risk of death in the hospital (HR: 0.5, 95% CI: 0.28–0.87, p = 0.014). We further confirmed the curve-like relationship between T-lowest and in-hospital mortality using restricted cubic splines. The mortality is lowest when the T-lowest is close to 36.5 °C, and the risk of death is increased when the temperature is lower or higher than that. Our study demonstrates that in-hospital mortality is associated with T-lowest. Patients with non-traumatic SAH are at increased risk of death if their body temperature on the first day of ICU admission is too low.

Impact of renal function variability on long-term prognosis in ischemic stroke patients with atrial fibrillation.

Although renal dysfunction is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) following stroke, the impact of renal function variability is unclear. This study aimed to assess the association between renal function variability and various adverse clinical outcomes in patients with transient ischemic attack (TIA)/ischemic stroke and atrial fibrillation (AF). We conducted a population-based study and retrospectively identified patients hospitalized with a diagnosis of TIA/ischemic stroke and AF during 2016-2020 using the Clinical Data Analysis and Reporting System of Hong Kong. Serial serum creatinine tested upon the onset of TIA/ischemic stroke and during their subsequent follow-up was collected. Renal function variability was calculated using the coefficient of variation of the estimated glomerular filtration rate (eGFR). Clinical endpoints that occurred during the study period were captured and included ischemic stroke/systemic embolism, intracerebral hemorrhage (ICH), total bleeding, major adverse cardiovascular events (MACE), cardiovascular, non-cardiovascular, and all-cause mortality. Competing risk regression and Cox proportional hazard regression models were used to assess the associations of renal function variability with the outcomes of interest. A total of 3,809 patients (mean age 80 ± 10 years, 43% men) who satisfied the inclusion and exclusion criteria were followed up for a mean of 2.5 ± 1.5 years (9,523 patient-years). The mean eGFR was 66 ± 22 mL/min/1.73 m2 at baseline, and the median number of renal function tests per patient during the follow-up period was 20 (interquartile range 11-35). After accounting for potential confounders, a greater eGFR variability was associated with increased risks of recurrent ischemic stroke/systemic embolism [fully adjusted subdistribution hazard ratio 1.11, 95% confidence interval (CI) 1.03-1.20], ICH (1.17, 1.01-1.36), total bleeding (1.13, 1.06-1.21), MACE (1.22, 1.15-1.30), cardiovascular (1.49, 1.32-1.69), non-cardiovascular (1.43, 1.35-1.52), and all-cause mortality (fully adjusted hazard ratio 1.44, 1.39-1.50). Visit-to-visit renal function variability is independently associated with adverse clinical outcomes in TIA/ischemic stroke patients with AF. Further large-scale studies are needed to validate our results.

Convalescent Growth Differentiation Factor-15 and Long-Term Outcomes after an Acute Coronary Syndrome.

Growth differentiation factor-15 (GDF-15) has been shown to be associated with adverse clinical outcomes in patients after an acute coronary syndrome when measured soon after an event. Although dynamic in the acute phase after myocardial injury, GDF-15 has been shown to remain stable during convalescence. In this study, we aimed to assess the value of GDF-15 as a long-term prognostic marker for clinical outcomes when measured in the convalescent phase following an acute coronary syndrome. GDF-15 concentrations were measured in 1945 patients who were recruited between 2002 and 2009 to the Coronary Disease Cohort Study. For this analysis, follow-up was curtailed at 10 years and association of GDF-15 with all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure hospitalizations were assessed with multivariate Cox proportional hazard regression analysis. After 10 years of follow-up, there were 648 deaths (348 from cardiovascular causes), 500 admissions for myocardial infarction, and 436 for heart failure. Four-month convalescent GDF-15 demonstrated a robust independent association with all endpoints, which remained after adjustment for Global Registry of Acute Coronary Events score and other convalescent biomarkers. When compared to the lowest quartile of GDF-15 concentrations, those in the highest quartile had a 3-fold increased risk of all-cause death. Convalescent plasma GDF-15 is a strong and independent predictor of 10-year all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure admission following an acute coronary syndrome. ACTRN12605000431628.

Coronary artery calcification score as a prognostic indicator for COVID-19 mortality: evidence from a retrospective cohort study in Iran

Background: Coronary artery calcification (CAC) has been established as an independent risk factor for major adverse cardiovascular events. Nevertheless, the effect of CAC on in-hospital mortality and adverse clinical outcomes in patients with COVID-19 has yet to be determined. Objective: To investigate the association between CAC score and in-hospital mortality of COVID-19 patients Method: This retrospective cohort study was conducted across tertiary hospitals of University of Medical Sciences in Babol, a northern city in Iran, and enroled 551 confirmed COVID-19 patients with definitive clinical outcomes of death or discharge between March and October 2021. Demographic and clinical data, along with chest computed tomography (CT) findings and CAC score on admission, were systematically collected. The study utilized logistic regression analysis and Kaplan-Meier plots to explore the association between CAC score and in-hospital death and adverse clinical outcomes. Results: The mean age was 60.05±12.8. A significant difference regarding CAC score, age, history of hypertension, hyperlipidemia, cardiovascular diseases, and respiratory diseases among survivors and non-survivors was observed; however, gender was not found to be different. Furthermore, in multivariate analysis, CAC score greater than or equal to 400 [odds ratio (OR): 4.2, 95% CI: 1.70–10.33, P value: 0.002], hospitalization time (OR: 1.31, 95% CI: 1.13–1.53, P value &lt; 0.001), length of ICU stay (OR: 2.02, 95% CI: 1.47–2.77, P value &lt; 0.001), severe or critical COVID-19 severity in time of admission (95% CI: 1.79–18.29, P value: 0.003), and history of respiratory diseases (95% CI: 2.18–40, P value: 0.003) were found to be associated with higher odds of in-hospital mortality. Log-rank test also revealed a significant difference regarding the time of admission to death between patients with CAC score greater than or equal to 400 and those with CAC score less than 400 (P value &lt; 0.001). Conclusion: Elevated CAC score is a crucial risk factor linked to in-hospital mortality and unfavourable clinical results in confirmed COVID-19 patients. This finding emphasizes the need for careful monitoring of individuals with high CAC scores.

Triglyceride to high-density lipoprotein cholesterol ratio associated with long-term adverse clinical outcomes in patients deferred revascularization following fractional flow reserve

BackgroundGuidelines on coronary intermediate lesions strongly recommend deferred revascularization after detecting a normal fractional flow reserve (FFR). Researches about triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) on cardiovascular diseases has also been well conducted. However, the association of TG/HDL-C and long-term adverse clinical outcomes remains unknown for patients deferred revascularization following FFR.MethodsThis study retrospectively included 374 coronary artery disease (CAD) patients with non-significant coronary lesions diagnosed by coronary angiography (CAG) and FFR. The main outcome measure was the combination of major adverse cardiovascular and cerebrovascular events (MACCEs). All patients were categorized into three subgroups in terms of TG/HDL-C tertiles (T1 < 0.96, 0.96 ≤ T2 < 1.58, T3 ≥ 1.58). Three different Cox regression models were utilized to reveal the association between TG/HDL-C and prevalence of MACCEs.Results47 MACCEs were recorded throughout a median monitoring period of 6.6 years. The Kaplan-Meier survival curves showed a higher MACCEs rate occurred in the higher TG/HDL-C group (5.6% vs. 12.9% vs. 19.4%, log-rank P < 0.01). After adjustment, patients in T3 suffered a 2.6-fold risk compared to the T1 group (T3 vs. T1: HR 2.55, 95% CI 1.05–6.21, P = 0.038; T2 vs. T1: HR 1.71, 95% CI 0.65–4.49, P = 0.075; P for trend = 0.001). The restricted cubic spline (RCS) analysis demonstrated that the HR for MACCEs rose as TG/HDL-C increased. Both the receiver operating characteristic (ROC) and time-dependent ROC proved the excellent predictive ability of TG/HDL-C.ConclusionThe study illustrates that TG/HDL-C correlates with the risk of MACCEs in CAD patients deferred revascularization following FFR. TG/HDL-C could serve as a dependable predictor of cardiovascular events over the long term in this population.

Adiponectin as a predictor of mortality and readmission in patients with community-acquired pneumonia: a prospective cohort study.

Adiponectin is secreted by adipocytes and is inversely associated with obesity. Given the association between low body mass index (BMI) and higher mortality risk after community-acquired pneumonia (CAP), we hypothesized that high adiponectin levels are associated with a higher risk of adverse clinical outcomes in patients with CAP. In a prospective cohort study of 502 patients hospitalized with CAP, adiponectin was measured in serum at admission. The associations between adiponectin and clinical outcomes were estimated with logistic regression analyses adjusted for age, sex, and measures of obesity (BMI, waist circumference or body fat percentage). Adiponectin was associated with higher 90-day mortality for each 1 μg/mL increase [OR 1.02, 95% CI (1.00, 1.04), p = 0.048] independent of age and sex. Likewise, adiponectin was associated with a higher risk of 90-day readmission for each 1 μg/mL increase [OR 1.02, 95% CI (1.01, 1.04), p = 0.007] independent of age and sex. The association between adiponectin and 90-day mortality disappeared, while the association with 90-day readmission remained after adjusting for adiposity. Adiponectin was positively associated with mortality and readmission. The association with mortality depended on low body fat, whereas the association with readmission risk was independent of obesity.

Abstract 3267: Understanding the role of dNTP pool on double-strand break and resistant to therapy in quiescent hypoxic glioblastoma

Abstract Glioblastoma (GBM) is the deadliest type of primary brain tumor. After surgical resection of GBM, chemotherapy and radiotherapy (RT) are used as treatment modalities to induce double-strand breaks (DSBs), the most cytotoxic and lethal form of DNA damage. However, an inadequate oxygen supply and the high metabolic demand in rapidly growing solid tumors like GBM result in severe hypoxic regions, contributing to altered cellular metabolism and resistance to these cancer therapies. These subpopulations of resistant and refractory hypoxic cancer cells are clinically significant as they lead to poor prognosis and adverse clinical outcomes in patients. Ionizing radiation (IR) and chemotherapeutics such as temozolomide induce DNA damage, such as base deletions, single-strand breaks (SSBs), and DSBs. Rapidly replicating cells are more sensitive to these therapeutic agents partly due to replication-induced conversion of SSB and other manageable damages to highly lethal DSB. A balanced deoxyribonucleoside triphosphate (dNTP) is crucial for DNA replication, repair, and maintenance of genomic stability. Cellular dNTP is mainly regulated by ribonucleotide reductase (RNR) and the SAM- and HD-domain-containing protein (SAMHD1). RNR boosts the cellular dNTP pool through the de novo synthesis, while SAMHD1 depletes the pool by hydrolyzing dNTPs. Also, previous studies have shown that hypoxic cancer cells have low dNTP levels due to oxygen dependency of its rate-limiting RNR enzyme, which could result in reduced DNA replication and cell cycle arrest. Here, we show the direct relationships between dNTP levels, DNA replication, and DSB induction in hypoxic GBM cancer cells, which is currently unknown. To bridge this knowledge gap, we exposed GBM cells to severe hypoxia and utilized cellular dNTP analysis to demonstrate that their dNTP pool can be elevated. Our results show that elevating the cellular dNTP pool relieved hypoxia-induced cell cycle arrest as determined by flow cytometry and increased their DNA replication. A single-cell microscopic analysis also revealed that increasing the dNTP pool significantly enhanced the induction of DSBs following exposure to IR and bleomycin. Furthermore, we detected an increased efficacy of DSB-inducing agents in hypoxic GBM, as demonstrated by apoptosis pathway activation. Our result suggests that increasing the intracellular dNTP pool in hypoxic GBM will stimulate DNA replication, increase genotoxin-induced DSB, and improve DSB-inducing therapeutic efficacy. In conclusion, this study provides a preclinical justification for using cellular dNTP modulation as a novel therapeutic strategy and an adjunct to classical DSB-inducing agents in hypoxic GBM. Citation Format: Edidiong R. Usoro, Dominique Monroe, Kristen Carver, Emily Steinbeck, Arilyn Williams, Shelby Aycox, Waaqo Daddacha. Understanding the role of dNTP pool on double-strand break and resistant to therapy in quiescent hypoxic glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3267.

Prognosis of anemic patients with atrial fibrillation undergoing percutaneous coronary intervention

BackgroundThere are limited data regarding whether anemia is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). MethodsPatients with AF undergoing PCI at 15 institutions between January 2015 and March 2021 were included in this analysis. Based on the baseline hemoglobin levels, moderate to severe anemia was defined as hemoglobin levels <11 g/dL, and mild anemia was defined as hemoglobin levels 11–12.9 g/dL for men and 11–11.9 g/dL for women. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, stent thrombosis, and stroke) and major bleeding events (BARC 3 or 5), were compared among patients with moderate/severe anemia, mild anemia, and no anemia. ResultsIn a total of 746 enrolled patients, 119 (16.0%) and 168 (22.5%) patients presented with moderate/severe and mild anemia. The incidence of MACE (22.5%, 11.0%, and 9.1%, log-rank p < 0.001), all-cause death (20.0%, 7.2%, and 4.8%, log-rank p < 0.001), and major bleeding events (10.7%, 6.5%, and 2.7%, log-rank p < 0.001) were the highest in the moderate/severe anemia group compared with the mild and no anemia groups. Multivariable Cox regression analyses determined moderate/severe anemia as an independent predictor for MACE (p = 0.008), all-cause death (p = 0.005), and major bleeding events (p = 0.031) at 1 year after PCI. ConclusionModerate/severe anemia was significantly associated with the higher incidence of MACE and all-cause death as well as major bleeding events compared with mild and no anemia in AF patients undergoing PCI.

Cases with Recurrent Hospitalization due to Unexplained Ileus: Paraduodenal Hernia

Internal hernia is one of the rare causes of surgical pathologies in the abdomen.Paraduodenal hernia (PDH) is the most frequent subtype of internal hernia. There are no specific clinical and laboratory findings for diagnosis. This situation may cause delays in diagnosis and adverse clinical outcomes in patients. Computed Tomography (CT) is an imaging method that can help in the diagnosis of internal hernia. A case report of our two patients who were followed up in the clinic, who had been hospitalized with similar complaints in the past and operated for paraduodenal hernia (PDH) has been prepared. Internal herniation is one of the pre-diagnoses that should be kept in mind, especially in the history of unexplained and recurrent hospitalization in patients with abdominal pain and signs of intestinal obstruction. Observation of hernia sac on CT and observing small intestinal loops trapped in it are the only objective findings that can help us in the diagnosis of internal herniation.

Abstract B020: Understanding the role of dNTP pool on double-strand break and resistance to therapy in quiescent hypoxic glioblastoma

Abstract Glioblastoma (GBM) is the deadliest type of primary brain tumor. After surgical resection, chemotherapy, and radiotherapy (RT) are used as treatment modalities to induce double-strand breaks (DSBs), the most cytotoxic and lethal form of DNA damage. However, an inadequate oxygen supply and the high metabolic demand in rapidly growing solid tumors like GBM result in severe hypoxic regions contributing to altered cellular metabolism and resistance to these cancer therapies. These subpopulations of resistant and refractory hypoxic cancer cells are clinically significant as they lead to poor prognosis and adverse clinical outcomes in patients. Ionizing radiation (IR) and chemotherapeutics such as temozolomide induce DNA damage, such as base deletions, single-strand breaks (SSBs), and DSBs. Rapidly replicating cells are more sensitive to these therapeutic agents partly due to replication-induced conversion of SSB and other manageable damages to highly lethal DSB. A balanced deoxyribonucleoside triphosphate (dNTP) is crucial for DNA replication, repair, and maintenance of genomic stability. Cellular dNTP is mainly regulated by ribonucleotide reductase (RNR) and the SAM- and HD-domain-containing protein (SAMHD1). RNR boosts the cellular dNTP pool through the de novo synthesis while SAMHD1 depletes the pool by hydrolyzing dNTPs. Previous studies have shown that hypoxic cancer cells have low dNTP levels due to oxygen dependency of its rate limiting RNR enzyme, which could result in reduced DNA replication and cell cycle arrest. Here, we show the direct relationships between dNTP levels, DNA replication, and DSB induction in hypoxic GBM cancer cells, which is currently unknown. To bridge this knowledge gap, we exposed GBM cells to severe hypoxia and utilized cellular dNTP analysis to demonstrate that their dNTP pool can be elevated. Our result shows that elevating cellular dNTP pool relieved hypoxia-induced cell cycle arrest as determined by flow cytometry and increased their DNA replication. A single cell microscopic analysis also revealed that increasing the dNTP pool significantly enhanced the induction of DSBs following exposure to IR and bleomycin. Furthermore, we detected an increased efficacy of DSB-inducing agents in hypoxic GBM as demonstrated by apoptosis pathway activation. Our result suggest that increasing the intracellular dNTP pool in hypoxic GBM will stimulate DNA replication, increase genotoxin-induced DSB, and improve DSB-inducing therapeutics' efficacy. This study provides a preclinical justification for using cellular dNTP modulation as a novel therapeutic strategy and an adjunct to classical DSB-inducing agents in hypoxic GBM. Citation Format: Edidiong R. Usoro, Dominique Monroe, Kristen Carver, Maya Jenkins, Emily Steinbeck, Arilyn Williams, Shelby Aycox, Waaqo Daddacha. Understanding the role of dNTP pool on double-strand break and resistance to therapy in quiescent hypoxic glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B020.

Prevalence, patterns, and impacts of multimorbidity on adverse clinical outcomes in chronic kidney disease: A systematic review

Background: Multimorbidity is the concurrent presence of two or more long-term health conditions in the same individual. It fragments healthcare delivery and affects quality of life. Chronic kidney disease (CKD) often occurs with multimorbidity. The prevalence of CKD is rising; however, there is a lack of evidence on the prevalence, patterns, and impacts of multimorbidity on adverse clinical outcomes in patients with CKD.&#x0D; Methods: This was a systematically conducted literature review. A search was conducted in EMBASE, MEDLINE, CINAHL, and SCOPUS (2019-2023). The main search terms were “chronic kidney disease” and “multimorbidity.” The eligibility criteria were observational studies with adult participants with all stages of CKD (CKD stages 1-5, including those on renal replacement therapy). The exposure was multimorbidity quantified by measures. All-cause mortality, kidney disease progression, hospitalisation, and cardiovascular events were outcomes. The Joanna Briggs Institute (JBI) checklist was used for the risk of bias assessment. Due to heterogeneity in design and methods, Jennie Popay’s narrative synthesis was used for data synthesis.&#x0D; Results: Of 6879 papers, nine papers met the inclusion criteria. Most studies included participants with all stages of CKD (CKD stage 1-5). The prevalence of multimorbidity ranged from 86.6% to 99.1%. Hypertension was the most prevalent comorbidity. The combination of concordant multimorbidity (hypertension, diabetes, and cardiovascular diseases) was highly prevalent. Multimorbidity was significantly associated with mortality, cardiovascular events, kidney disease progression, and hospitalisation. While older people had more multimorbidity burdens, younger patients with CKD were at a higher risk of death from multimorbidity. Severe CKD with clusters of cardiovascular diseases, diabetes, chronic pain, and depression was significantly associated with all-cause mortality.&#x0D; Conclusion: There are associations between multimorbidity and adverse clinical outcomes in patients with CKD. However, there is a lack of data on Black, Asian, and Minority Ethnic participants from low- and middle-income countries. Further research is needed to investigate the high prevalence of chronic pain and depression in chronic kidney disease.

Glycated Albumin and Adverse Clinical Outcomes in Patients With CKD: A Prospective Cohort Study

Rationale & ObjectiveHbA1c is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis dependent CKD population remains unknown. Study DesignProspective cohort study. Setting& Participants: 3110 participants with CKD from the Chronic Renal Insufficiency Cohort study. ExposureBaseline GA levels. OutcomesIncident end-stage kidney disease (ESKD), cardiovascular disease (CVD) events, and all-cause mortality. Analytical ApproachCox proportional hazards regression. ResultsParticipant characteristics included mean age 59.0 (SD 10.8) years; 1357 (43.6%) female; 1550 (49.8%) with diabetes. The median GA was 18.7 (interquartile range, 15.8-23.3)%. During an average 7.9-year follow-up, there were 980 ESKD events, 968 CVD events, and 1084 deaths. Higher GA levels were associated with greater risks of all outcomes, regardless of diabetes status: hazard ratios for ESKD, CVD, and death among participants with the highest quartile compared with quartile 2 (reference) were 1.42 (95%CI, 1.19-1.69), 1.67 (CI, 1.39-2.01), and 1.63 (CI, 1.37-1.94), respectively. The associations with CVD and death appeared J-shaped, with increased risk also seen at the lowest GA levels. Among patients with coexisting CKD and diabetes, the associations of GA with outcomes remained significant even after adjusting for HbA1c. For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA1c were added to models. LimitationsLack of longitudinal GA measurements; HbA1c measurements were largely unavailable in participants without diabetes. ConclusionsAmong patients with CKD, GA levels were independently associated with risks of ESKD, CVD, and mortality, regardless of diabetes status. GA added prognostic value to HbA1c among patients with coexisting CKD and diabetes.

Impact of multivessel versus single-vessel disease on the association between low diastolic blood pressure and mortality after acute myocardial infarction with revascularization.

Previous studies demonstrated a J-shaped relationship between low diastolic blood pressure (DBP) and adverse clinical outcomes in patients with acute myocardial infarction (AMI) that was sensitive to revascularization. Hypothesized herein, was that this relationship differs between patients with multivessel disease (MVD) and those with single-vessel disease due to differing degrees of myocardial ischemic burden. Among 9,983 AMI patients from the Korea Acute Myocardial Infarction Registry database who underwent percutaneous coronary intervention and were followed up for a median duration of 3.2 years, average on-treatment DBP was calculated at admission, discharge, and every scheduled visit and divided into these parameters: < 70 mmHg, 70-74 mmHg, 75-79 mmHg, and ≥ 80 mmHg. The relationship between average on-treatment DBP and clinical outcomes including all-cause death, cardiovascular (CV) death, non-CV death, and hospitalization for heart failure was analyzed using the Cox regression models adjusted for clinical covariates. In patients with MVD, all-cause death (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.06-2.04, p = 0.012) and CV death (HR: 1.59; 95% CI: 1.02-2.46, p = 0.027) were significantly increased in patients with a DBP < 70 mmHg, showing a J-shaped relationship. However, these findings were not significant for single-vessel disease. On a sensitivity analysis excluding subjects with a baseline SBP < 120 mmHg, an increased risk of a low DBP < 70 mmHg remained in MVD. The J-shaped relationship between low DBP and adverse clinical outcomes in AMI patients who underwent revascularization persisted in MVD, which has a high ischemic burden. These high-risk patients require cautious treatment.

The epigenetic downregulation of LncGHRLOS mediated by RNA m6A methylase ZCCHC4 promotes colorectal cancer tumorigenesis

Backgroundm6A modification is currently recognized as a major driver of RNA function that maintains cancer cell homeostasis. Long non-coding (Lnc) RNAs control cell proliferation and play an important role in the occurrence and progression of colorectal cancer (CRC). ZCCHC4 is a newly discovered m6A methyltransferase whose role and mechanism in tumors have not yet been elucidated.MethodsThe EpiQuik m6A RNA methylation kit was used to detect the level of total RNA m6A in six types of digestive tract tumors. The Kaplan-Meier method and receiver operating characteristic curve were used to evaluate the prognostic and diagnostic value of the newly discovered m6A methyltransferase, ZCCHC4, in CRC. The effects on CRC growth in vitro and in vivo were studied using gain- and loss-of-function experiments. The epigenetic mechanisms underlying ZCCHC4 upregulation in CRC were studied using RIP, MeRIP-seq, RNA pull-down, and animal experiments.ResultsWe reported that the ZCCHC4-LncRNAGHRLOS-KDM5D axis regulates the growth of CRC in vitro and in vivo. We found that ZCCHC4 was upregulated in primary CRC samples and could predict adverse clinical outcomes in patients with CRC. Mechanistically, ZCCHC4 downregulated LncRNAGHRLOS to promote CRC tumorigenesis. As a downstream molecule of LncRNAGHRLOS, KDM5D directly controls CRC cell proliferation, migration, and invasion.ConclusionThis study suggests that the ZCCHC4 axis contributes to the tumorigenesis and progression of CRC and that ZCCHC4 may be a potential biomarker for this malignancy.

Computed tomography-based radiomics model to predict adverse clinical outcomes in acute pulmonary embolism.

This preliminary study investigated the feasibility of a combined model constructed using radiomic features based on computed tomography (CT) and clinical features to predict adverse clinical outcomes in acute pulmonary embolism (APE). Currently, there is no widely recognized predictive model. Patients with confirmed APE who underwent CT pulmonary angiography were retrospectively categorized into good and poor prognosis groups. Seventy-four patients were randomized into a training (n = 51) or validation (n = 23) cohort. Feature extraction was performed using 3D-Slicer software. The least absolute shrinkage and selection operator regression was used to identify the optimal radiomics features and calculate the radiomics scores; subsequently, the radiomics model was developed. A combined predictive model was constructed based on radiomics scores and selected clinical features. The predictive efficacy of the three models (radiomics, clinical and combined) was assessed by plotting receiver operating characteristic curves. Furthermore, the calibration curves were graphed and the decision curve analysis was performed. Four radiomic features were screened to calculate the radiomic score. Right ventricular to left ventricular ratio (RV/LV) ≥ 1.0 and radiomics score were independent risk factors for adverse clinical outcomes. In the training and validation cohorts, the areas under the curve (AUCs) for the RV/LV ≥ 1.0 (clinical) and radiomics score prediction models were 0.778 and 0.833 and 0.907 and 0.817, respectively. The AUCs for the combined model of RV/LV ≥ 1.0 and radiomics score were 0.925 and 0.917, respectively. The combined and radiomics models had high clinical assessment efficacy for predicting adverse clinical outcomes in APE, demonstrating the clinical utility of both models. Calibration curves exhibited a strong level of consistency between the predictive and observed probabilities of poor and good prognoses in the combined model. The combined model of RV/LV ≥ 1.0 and radiomics score based on CT could accurately and non-invasively predict adverse clinical outcomes in patients with APE.