The Epidemiology of Berry Consumption and Association of Berry Consumption with Diet Quality and Cardiometabolic Risk Factors in United States Adults: The National Health and Nutrition Examination Survey, 2003-2018.

BACKGROUND: Berries are rich in important nutrients and bioactive compounds, which could potentially contribute to maintenance of normal lipid and glucose profiles. OBJECTIVE: We reported the epidemiology of berry consumption and examined associations of berry consumption with diet quality [measured by Healthy Eating Index (HEI-2015)] and levels of cardiometabolic risk factors, including body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), glycated hemoglobin, and fasting biomarkers: triglycerides, low-density lipoprotein cholesterol (LDL cholesterol), glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: We evaluated 33,082 adults (aged ≥20 y) using two 24-h diet recalls from National Health and Nutrition Examination Survey (2003-2018). Multivariable linear regression models were applied to examine the associations of total and individual berry intake with diet quality and cardiometabolic risk factors using appropriate sample weights. RESULTS: Approximately 25 % of the United States adults consumed berries (0.08 ± 0.003 cup-equivalents/d), representing ∼10 % of the daily mean total fruit intake. Among berry consumers, the mean intake of strawberries (0.31 ± 0.01 cup-equivalents) was higher than for other berries. Berry consumers had a significantly higher HEI-2015 score than nonconsumers (mean HEI-2015 score = 58.8 compared with 52.3, P < 0.0001). Berry consumers had significantly lower concentrations of cardiometabolic indices than nonconsumers, including BMI, WC, SBP, total cholesterol, LDL cholesterol, triglycerides, fasting insulin, HOMA-IR, and higher mean HDL cholesterol, after adjusting for sociodemographic, lifestyle, and dietary confounders (all P < 0.05). CONCLUSIONS: United States adult berry consumers had a higher diet quality and lower concentrations of cardiometabolic risk factors, suggesting a favorable role for berries in diets and cardiometabolic disease prevention in United States adult population.

Consumption of Berries and Flavonoids in Relation to Mortality in NHANES, 1999-2014.

BACKGROUND: Berries are foods that are abundant in nutrients, especially flavonoids, that promote good health; however, the effects of total berries on mortality are not well characterized. OBJECTIVES: We evaluated whether intakes of total berries and specific berry types including blueberries, strawberries, cranberries, flavonoids, and subclasses of flavonoids (anthocyanidins, flavonols, flavones, flavanones, flavan-3-ols, and isoflavones) in relation to mortality risk in United States adults. METHODS: A nationally representative sample of the United States adult population was obtained using data from the 1994-2014 NHANES (n = 37,232). Intake of berries was estimated using 24-h food recalls (1999-2014), and flavonoids intake was calculated using the matched USDA's expanded flavonoid database. Mortality outcomes based on 8 y of follow-up were obtained using linked death certificates. RESULTS: Compared with nonconsumers, the multivariable-adjusted hazard ratio for all-cause mortality was 0.79 [95% confidence intervals (CI): 0.7, 0.89] for any berry consumption, 0.86 (0.75, 0.99) for strawberry consumption 0.79 (0.66, 0.95) for blueberries, and 0.69 (0.51, 0.93) for cranberries. Compared with the lower median of intake, risk of all-cause mortality for greater intake was 0.85 (0.74, 0.97) for total flavonoids, 0.85 (0.76, 0.95) for anthocyanidins, 0.9 (0.82, 0.99) for flavan-3-ols, 0.89 (0.79, 0.9) for flavanols, and 0.89 (0.8, 0.99) for flavones. There was a dose-response relationship between intakes of total flavonoids, anthocyanidins, and flavones and lower all-cause mortality risks (Ptrend < 0.05). Risk for cardiometabolic mortality was 0.75 (0.58, 0.98) for berry consumers and 0.49 (0.25, 0.98) for cranberry consumers. For respiratory disease mortality, risk was 0.41 (0.2, 0.86), compared with blueberry nonconsumers. CONCLUSION: Higher intakes of berries and flavonoids were associated with a lower overall mortality risk in adult Americans. Few adults regularly consume berries, indicating that increased intake of berries and flavonoid-rich foods may be beneficial to health.

Exercise training improves serum biomarkers of liver fibroinflammation in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND AND AIMS: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. METHODS: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. RESULTS: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (-61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. CONCLUSION: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weight-neutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level.

Exercise improves surrogate measures of liver histological response in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. METHODS: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. RESULTS: Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). CONCLUSION: Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.

Can machine learning predict late seizures after intracerebral hemorrhages? Evidence from real-world data.

INTRODUCTION: Intracerebral hemorrhage represents 15 % of all strokes and it is associated with a high risk of post-stroke epilepsy. However, there are no reliable methods to accurately predict those at higher risk for developing seizures despite their importance in planning treatments, allocating resources, and advancing post-stroke seizure research. Existing risk models have limitations and have not taken advantage of readily available real-world data and artificial intelligence. This study aims to evaluate the performance of Machine-learning-based models to predict post-stroke seizures at 1 year and 5 years after an intracerebral hemorrhage in unselected patients across multiple healthcare organizations. DESIGN/METHODS: We identified patients with intracerebral hemorrhage (ICH) without a prior diagnosis of seizures from 2015 until inception (11/01/22) in the TriNetX Diamond Network, using the International Classification of Diseases, Tenth Revision (ICD-10) I61 (I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9). The outcome of interest was any ICD-10 diagnosis of seizures (G40/G41) at 1 year and 5 years following the first occurrence of the diagnosis of intracerebral hemorrhage. We applied a conventional logistic regression and a Light Gradient Boosted Machine (LGBM) algorithm, and the performance of the model was assessed using the area under the receiver operating characteristics (AUROC), the area under the precision-recall curve (AUPRC), the F1 statistic, model accuracy, balanced-accuracy, precision, and recall, with and without seizure medication use in the models. RESULTS: A total of 85,679 patients had an ICD-10 code of intracerebral hemorrhage and no prior diagnosis of seizures, constituting our study cohort. Seizures were present in 4.57 % and 6.27 % of patients within 1 and 5 years after ICH, respectively. At 1-year, the AUROC, AUPRC, F1 statistic, accuracy, balanced-accuracy, precision, and recall were respectively 0.7051 (standard error: 0.0132), 0.1143 (0.0068), 0.1479 (0.0055), 0.6708 (0.0076), 0.6491 (0.0114), 0.0839 (0.0032), and 0.6253 (0.0216). Corresponding metrics at 5 years were 0.694 (0.009), 0.1431 (0.0039), 0.1859 (0.0064), 0.6603 (0.0059), 0.6408 (0.0119), 0.1094 (0.0037) and 0.6186 (0.0264). These numerical values indicate that the statistical models fit the data very well. CONCLUSION: Machine learning models applied to electronic health records can improve the prediction of post-hemorrhagic stroke epilepsy, presenting a real opportunity to incorporate risk assessments into clinical decision-making in post-stroke care clinical care and improve patients' selection for post-stroke epilepsy research.

Evaluating the relationship between physical activity and quality of life in a racially diverse sample of breast cancer survivors.

PURPOSE: Physical activity (PA) has been shown to improve quality of life (QoL) in predominantly White cancer survivors. Very few studies have examined the association between PA and QoL among Black breast cancer survivors (BCS). We investigated the association between PA and multiple QoL domains and the effects of race on the proposed association in a racially diverse group of BCS. METHODS: This was an exploratory study using secondary data from a completed 12-month randomized controlled  trial (RCT). Mixed effects models were tested on a subset of participants in the control and exercise groups of the RCT. The primary outcomes were changes in the QoL domains (baseline to 12 months post baseline). RESULTS: There were 173 participants included in this analysis, averaging 59 years of age; about 33% of the participants were Black women. There were no significant differences in the QoL outcomes between the control and exercise groups at 12 months post baseline. Race was not a significant moderator. Exercise improved emotional/mental wellbeing and body image as it relates to social barriers at 12 months post baseline in Black and White BCS, but the changes in these outcomes were only statistically significant in White BCS (p < 0.05). CONCLUSIONS: Results show that exercise can improve multiple QoL domains over time in Black BCS. However, the significance of the effect on QoL was isolated to White BCS. The small sample size in Black women could constrain the statistical significance of observed effects. Future studies are warranted to assess associations between exercise and QoL in larger samples of Black women.

Exploring Quality of Life Experiences and Concerns of Black Breast Cancer Survivors: a Narrative Approach.

Black breast cancer survivors (BCS) in comparison with White BCS are more likely to experience suboptimal quality of life (QoL). QoL is a multi-dimensional concept that focuses on different aspects of well-being (e.g., emotional well-being). There is limited evidence on the perspectives and experiences of QoL (e.g., the influence of breast cancer on QoL) and the QoL concerns (e.g., negative perceptions of body appearance) among Black BCS. The purpose of this study was to explore the QoL experiences and QoL concerns of Black BCS. Primary data was collected in semi-structured interviews and analyzed using a thematic analysis. A narrative approach (detailed stories or life experiences of a small group of people) was used to better understand the research topic among the target group. Ferrell's Conceptual Framework on QoL in Breast Cancer was used to guide the development of the interview questions, codes, and themes. There were 10 Black BCS, averaging 58 years of age. Two coders achieved a moderate level of agreement (i.e., Kappa) of 0.77. Five major themes were identified: defining QoL (what QoL means to them), behavioral changes (e.g., altering behaviors due to cancer), phases of cancer (e.g., breast cancer diagnosis), QoL experiences and factors affecting QoL, and impactful statements from cancer survivors (other meaningful information shared by the participants). The survivors reported multiple QoL concerns and body image issues. The study findings warrant cancer education interventions or programs to address the relevant survivorship issues of Black BCS.

The ASSESS-AKI Study found urinary epidermal growth factor is associated with reduced risk of major adverse kidney events.

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients.

Exercise Training Is Associated With Treatment Response in Liver Fat Content by Magnetic Resonance Imaging Independent of Clinically Significant Body Weight Loss in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Exercise training is crucial in the management of nonalcoholic fatty liver disease (NAFLD); however, whether it can achieve clinically meaningful improvement in liver fat is unclear. We investigated the association between exercise training and the achievement of validated thresholds of MRI-measured treatment response. METHODS: Randomized controlled trials in adults with NAFLD were identified through March 2022. Exercise training was compared with no exercise training. The primary outcome was ≥30% relative reduction in MRI-measured liver fat (threshold required for histologic improvement in nonalcoholic steatohepatitis activity, nonalcoholic steatohepatitis resolution, and liver fibrosis stage). Different exercise doses were compared. RESULTS: Fourteen studies (551 subjects) met inclusion criteria (mean age 53.3 yrs; body mass index 31.1 kg/m 2 ). Exercise training subjects were more likely to achieve ≥30% relative reduction in MRI-measured liver fat (odds ratio 3.51, 95% confidence interval 1.49-8.23, P = 0.004) than those in the control condition. An exercise dose of ≥750 metabolic equivalents of task min/wk (e.g., 150 min/wk of brisk walking) resulted in significant treatment response (MRI response odds ratio 3.73, 95% confidence interval 1.34-10.41, P = 0.010), but lesser doses of exercise did not. Treatment response was independent of clinically significant body weight loss (>5%). DISCUSSION: Independent of weight loss, exercise training is 3 and a half times more likely to achieve clinically meaningful treatment response in MRI-measured liver fat compared with standard clinical care. An exercise dose of at least 750 metabolic equivalents of task-min/wk seems required to achieve treatment response. These results further support the weight-neutral benefit of exercise in all patients with NAFLD.

Integrated Analysis of Blood and Urine Biomarkers to Identify Acute Kidney Injury Subphenotypes and Associations With Long-term Outcomes.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes. STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study. PREDICTORS: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes. OUTCOME: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years. ANALYTICAL APPROACH: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P=0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes. LIMITATIONS: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable. CONCLUSIONS: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI. PLAIN-LANGUAGE SUMMARY: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH.

BACKGROUND AND AIMS: NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study. APPROACH AND RESULTS: We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH. Patients were randomly assigned (2:1 ratio) to receive either an exercise training program or standard clinical care. The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1) level, an established thrombotic biomarker. Twenty-eight patients were randomly assigned (18 exercise training and 10 standard clinical care). PAI-1 level was significantly decreased by exercise training when compared to standard clinical care (-40 ± 100 vs. +70 ± 63 ng/ml; p = 0.02). Exercise training decreased MRI proton density fat fraction (MRI-PDFF; -4.7 ± 5.6 vs. 1.2 ± 2.8% absolute liver fat; p = 0.01); 40% of exercise subjects had a ≥30% relative reduction in MRI-PDFF (histological response threshold) compared to 13% for standard of care (p < 0.01). Exercise training improved fitness (VO2 peak, +3.0 ± 5.6 vs. -1.8 ± 5.1 ml/kg/min; p = 0.05) in comparison to standard clinical care. CONCLUSIONS: This clinical trial showed that, independent of weight loss or dietary change, exercise training resulted in a significantly greater decrease in thrombotic risk than standard clinical care in patients with NASH, in parallel with MRI-PDFF reduction and improvement in fitness. Future studies are required to determine whether exercise training can directly impact patient outcomes and lower rates of TE.

Urine eosinophil-derived neurotoxin: A potential marker of activity in select eosinophilic disorders.

BACKGROUND: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. METHODS: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. RESULTS: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. CONCLUSIONS: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

Tackling dynamic prediction of death in patients with recurrent cardiovascular events.

In the field of cardiovascular disease, recurrent events such as stroke or myocardial infarction (MI) are often encountered, leading to an increase in the risk of death. Accurately evaluating the prognosis of patients and dynamically predicting the risk of death by considering the historical recurrent events can improve medical decisions and lead to better health care outcomes. Recently proposed joint modeling approaches within the Bayesian framework have inspired the development of a dynamic prediction tool, which can be applied for subject-level prediction of death with implementation in software packages. The prediction model incorporates subject heterogeneity with subject-level random effects that account for unobserved time-invariant factors and an extra copula function capturing the part caused by unmeasured time-dependent factors. Thereafter, given the prespecified landmark time t ' $$ {t}^{\prime } $$ , the survival probability for a prediction horizon time of interest t $$ t $$ can be estimated for each individual. The prediction accuracy is assessed by time-dependent receiving operating characteristic curve and the area under the curve and the Brier score with calibration plots is compared to traditional joint frailty models. Finally, the tool is applied to patients with multiple attacks of stroke or MI in the Cardiovascular Health study and the Atherosclerosis Risk in Communities study for illustration.

Factors associated with pediatric febrile illnesses in 27 countries of Sub-Saharan Africa.

BACKGROUND: Evidence on the relative importance of various factors associated with febrile illness in children and their heterogeneity across countries can inform the prevention, identification, and management of communicable diseases in resource-limited countries. The objective of the study is to assess the relative significance of factors associated with childhood febrile illness in 27 sub-Saharan African countries. METHODS: This cross-sectional study of 298,327 children aged 0 to 59 months assessed the strengths of associations of 18 factors with childhood fevers, using Demographic and Health Surveys (2010-2018) from 27 sub-Saharan African countries. A total of 7 child level factors (i.e., respiratory illness, diarrhea, breastfeeding initiation; vitamin A supplements; child's age; full vaccination; sex), 5 maternal factors (maternal education; maternal unemployment; antenatal care; maternal age, and maternal marriage status) and 6 household factors (household wealth; water source; indoor pollution, stool disposal; family planning needs and rural residence) were assessed. Febrile illness was defined as the presence of fever in 2 weeks preceding the survey. RESULTS: Among the 298,327 children aged 0 to 59 months included in the analysis, the weighted prevalence of fever was 22.65% (95% CI, 22.31%-22.91%). In the pooled sample, respiratory illness was the strongest factor associated with fever in children (adjusted odds ratio [aOR], 5.46; 95% CI, 5.26-5.67; P < .0001), followed by diarrhea (aOR, 2.96; 95% CI, 2.85-3.08; P < .0001), poorest households (aOR, 1.33; 95% CI,1.23-1.44; P < .0001), lack of maternal education (aOR, 1.25; 95% CI, 1.10-1.41; P < .0001), and delayed breastfeeding (aOR, 1.18; 95% CI, 1.14-1.22; P < .0001. Febrile illnesses were more prevalent in children older than >6 months compared to those 6 months and younger. Unsafe water, unsafe stool disposal, and indoor pollution were not associated with child fever in the pooled analysis but had a large country-level heterogeneity. CONCLUSIONS: Major causes of fevers in sub-Saharan Africa could be attributed to respiratory infections and possibly viral infections, which should not be treated by antimalarial drugs or antibiotics. Point-of-care diagnostics are needed to identify the pathogenic causes of respiratory infections to guide the clinical management of fevers in limited-resource countries.

Associations of small vessel disease and acute symptomatic seizures in ischemic stroke patients.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs), markers of small vessel disease are frequent in ischemic stroke, yet the association with acute symptomatic seizures (ASS) has not been well characterized. METHODS: A retrospective cohort of hospitalized patients with anterior circulation ischemic stroke. The association of CMBs with acute symptomatic seizures was assessed using a logistic regression model and causal mediation analysis. RESULTS: Of 381 patients, 17 developed seizures. Compared with patients without CMBs, those with CMBs had a three-fold higher unadjusted odds of seizures (unadjusted OR: 3.84, 95% 1.16-12.71, p = 0.027). After adjusting for confounders such as stroke severity, cortical infarct location, and hemorrhagic transformation, the association between CMBs and ASS was attenuated (adjusted OR: 3.11, 95%CI: 0.74-11.03, p = 0.09). The association was not mediated by stroke severity. CONCLUSION: In this cohort of hospitalized patients with anterior circulation ischemic stroke, CMBs were more likely to be found in patients with ASS than those without ASS, an association that was attenuated when accounting for stroke severity, cortical infarct location, and hemorrhagic transformation. Evaluation of the long-term risk of seizures associated with CMBs and other markers of small vessel disease is warranted.

Short-term and intermediate-term fine particulate air pollution are synergistically associated with habitual sleep variability in adolescents - A cross-sectional study.

BACKGROUND: Both air pollution and poor sleep have been associated with increased risk of cardiovascular diseases. However, the association between air pollution and sleep health, especially among adolescents, is rarely investigated. METHODS: To investigate the association between fine particulate (PM2.5) air pollution and habitual sleep patterns, we analyzed data obtained from 246 adolescents who participated in the Penn State Child Cohort follow-up examination. We collected their individual-level 24-h (short-term) PM2.5 concentration by using a portable monitor. We estimated their residential-level PM2.5 concentration during the 60-day period prior to the examination (intermediate-term) using a kriging approach. Actigraphy was used to measure participants' sleep durations for seven consecutive nights. Habitual sleep duration (HSD) and sleep variability (HSV) were calculated as the mean and SD of the seven-night sleep duration. Multivariable-adjusted linear regression models were used to assess the association between PM2.5 exposures and HSD/HSV. An interaction between short-term and intermediate-term PM2.5 was created to explore their synergistic associations with HSD/HSV. RESULTS: Elevated short-term and intermediate-term PM2.5 exposure were significantly (p < 0.05) associated with higher HSV, but not HSD. Specifically, the mean (95% CI) increase in HSV associated with 1 SD higher 24-h (26.3 µg/m3) and 60-day average (2.2 µg/m3) PM2.5 were 14.6 (9.4, 14.8) and 4.9 (0.5, 9.2) minutes, respectively. In addition, there was a synergistic interaction (p = 0.08) between short-term and intermediate-term PM2.5 exposure on HSV, indicative that the association between intermediate-term PM2.5 and HSV became stronger as short-term PM2.5 increases, and vice versa. CONCLUSION: Short-term individual-level and intermediate-term residential-level PM2.5 exposures are adversely and synergistically associated with increased sleep variability, an indicator of instability of sleep quantity, in adolescents. Through such an association with sleep pattern, PM2.5 air pollution may increase long-term cardiometabolic risks.

Physical Activity and Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Physical activity offers promise to protect against multiple non-hepatic primary cancers. We performed a systematic review to quantify the association between physical activity and hepatocellular carcinoma (HCC) risk. METHODS: We searched the Cochrane Library, Embase, Medline and trial registries through December 2020 for studies that measured physical activity levels in adults at risk for HCC. The primary outcome was HCC. Subgroup analysis was performed limiting to vigorous physical activity. Proportions and random-effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Seven studies met inclusion criteria, comprising 777,662 subjects (median age 55 years; 55% female). Greater amounts of physical activity were associated with less HCC (OR 0.65, 95% CI 0.45-0.95, p = 0.03) compared to lower amounts. Vigorous physical activity was associated with even less HCC (OR 0.62, 95% CI 0.49-0.79, p < 0.01). CONCLUSIONS: This meta-analysis demonstrates that greater amounts of physical activity are associated with lower odds of HCC. These results support the use of regular physical activity as an effective way to prevent HCC and provide helpful data to support a for future exercise-based interventional study to better define the optimal exercise prescription for patients at risk for primary liver cancer.

The association between proton pump inhibitor use and risk of post-hospitalization acute kidney injury: a multicenter prospective matched cohort study.

BACKGROUND: Proton Pump Inhibitors (PPI) are among the most commonly used drugs to treat acid-related gastrointestinal disorders in the USA. Although PPI use has been linked to acute interstitial nephritis, the side effects of post-hospitalization acute kidney injury (AKI) and the progression of kidney disease still are controversial. We conducted a matched cohort study to examine the associations between PPI use and the side effects, especially in post-hospitalization AKI. METHODS: We investigated 340 participants from the multicenter, prospective, matched-cohort ASSESS-AKI study, which enrolled participants from December 2009 to February 2015. After the baseline index hospitalization, follow-up visits were conducted every six months, and included a collection of self-reported PPI use by participants. Post-hospitalization AKI was defined as the percentage increase from the nadir to peak inpatient SCr value was ≥ 50% and/or absolute increase ≥ 0.3 mg/dL in peak inpatient serum creatinine compared with baseline outpatient serum creatinine. We applied a zero-inflated negative binomial regression model to test the relationship between PPI use and post-hospitalization AKI. Stratified Cox proportional hazards regression models also were conducted to examine the association between PPI use and the risk of progression of kidney disease. RESULTS: After controlling for demographic variables, baseline co-morbidities and drug use histories, there was no statistically significant association between PPI use and risk of post-hospitalization AKI (risk ratio [RR], 0.91; 95% CI, 0.38 to 1.45). Stratified by AKI status at baseline, no significant relationships were confirmed between PPI use and the risk of recurrent AKI (RR, 0.85; 95% CI, 0.11 to 1.56) or incidence of AKI (RR, 1.01; 95% CI, 0.27 to 1.76). Similar non-significant results also were observed in the association between PPI use and the risk of progression of kidney diseases (Hazard Ratio [HR], 1.49; 95% CI, 0.51 to 4.36). CONCLUSION: PPI use after the index hospitalization was not a significant risk factor for post-hospitalization AKI and progression of kidney diseases, regardless of the AKI status of participants at baseline.

Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury.

BACKGROUND: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. METHODS: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. RESULTS: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. CONCLUSIONS: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.