Disease Outcome Research Articles

Severity predictors for multisystemic inflammatory syndrome in children after SARS-CoV-2 infection in Vietnam

Multisystemic inflammatory syndrome in children (MIS-C) might manifest in a broad spectrum of clinical scenarios, ranging from mild features to multi-organ dysfunction and mortality. However, this novel entity has a heterogenicity of data regarding prognostic factors associated with severe outcomes. The present study aimed to identify independent predictors for severity by using multivariate regression models. A total of 391 patients (255 boys and 136 girls) were admitted to Vietnam National Children’s Hospital from January 2022 to June 2023. The median age was 85 (range: 2–188) months, and only 12 (3.1%) patients had comorbidities. 161 (41.2%) patients required PICU admission, and the median PICU LOS was 4 (2–7) days. We observed independent factors related to PICU admission, including CRP ≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge $$\\end{document} 50 (mg/L) (OR 2.52, 95% CI 1.39–4.56, p = 0.002), albumin ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 30 (g/L) (OR 3.18, 95% CI 1.63–6.02, p = 0.001), absolute lymphocyte count ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 2 (× 109/L) (OR 2.18, 95% CI 1.29–3.71, p = 0.004), ferritin ≥ 300 (ng/mL) (OR 2.35, 95% CI 1.38–4.01), p = 0.002), and LVEF < 60 (%) (OR 2.48, 95% CI 1.28–4.78, p = 0.007). Shock developed in 140 (35.8%) patients, especially for those decreased absolute lymphocyte ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 2 (× 109/L) (OR 2.48, 95% CI 1.10–5.61, p = 0.029), albumin ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 30 (g/L) (OR 2.53, 95% CI 1.22–5.24, p = 0.013), or LVEF < 60 (%) (OR 2.24, 95% CI 1.12–4.51, p = 0.022). In conclusion, our study emphasized that absolute lymphocyte count, serum albumin, CRP, and LVEF were independent predictors for MIS-C severity. Further well-designed investigations are required to validate their efficacy in predicting MIS-C severe cases, especially compared to other parameters. As MIS-C is a new entity and severe courses may progress aggressively, identifying high-risk patients optimizes clinicians' follow-up and management to improve disease outcomes.

Restoring Skeletal Muscle Health through Exercise in Breast Cancer Patients and after Receiving Chemotherapy

Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients’ quality of life. However, a “one size fits all” approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.

Restoring Skeletal Muscle Health through Exercise in Breast Cancer Patients and after Receiving Chemotherapy

Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients’ quality of life. However, a “one size fits all” approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.

Severity predictors for multisystemic inflammatory syndrome in children after SARS-CoV-2 infection in Vietnam

Multisystemic inflammatory syndrome in children (MIS-C) might manifest in a broad spectrum of clinical scenarios, ranging from mild features to multi-organ dysfunction and mortality. However, this novel entity has a heterogenicity of data regarding prognostic factors associated with severe outcomes. The present study aimed to identify independent predictors for severity by using multivariate regression models. A total of 391 patients (255 boys and 136 girls) were admitted to Vietnam National Children’s Hospital from January 2022 to June 2023. The median age was 85 (range: 2–188) months, and only 12 (3.1%) patients had comorbidities. 161 (41.2%) patients required PICU admission, and the median PICU LOS was 4 (2–7) days. We observed independent factors related to PICU admission, including CRP ≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge $$\\end{document} 50 (mg/L) (OR 2.52, 95% CI 1.39–4.56, p = 0.002), albumin ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 30 (g/L) (OR 3.18, 95% CI 1.63–6.02, p = 0.001), absolute lymphocyte count ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 2 (× 109/L) (OR 2.18, 95% CI 1.29–3.71, p = 0.004), ferritin ≥ 300 (ng/mL) (OR 2.35, 95% CI 1.38–4.01), p = 0.002), and LVEF < 60 (%) (OR 2.48, 95% CI 1.28–4.78, p = 0.007). Shock developed in 140 (35.8%) patients, especially for those decreased absolute lymphocyte ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 2 (× 109/L) (OR 2.48, 95% CI 1.10–5.61, p = 0.029), albumin ≤\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\le $$\\end{document} 30 (g/L) (OR 2.53, 95% CI 1.22–5.24, p = 0.013), or LVEF < 60 (%) (OR 2.24, 95% CI 1.12–4.51, p = 0.022). In conclusion, our study emphasized that absolute lymphocyte count, serum albumin, CRP, and LVEF were independent predictors for MIS-C severity. Further well-designed investigations are required to validate their efficacy in predicting MIS-C severe cases, especially compared to other parameters. As MIS-C is a new entity and severe courses may progress aggressively, identifying high-risk patients optimizes clinicians' follow-up and management to improve disease outcomes.

Phenotypes of COVID-19-associated dysautonomia in patients requiring veno-venous extracorporeal membrane oxygenation

Background. Patients with novel coronavirus infection (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) are typically prone to hemodynamic disorders of various severity. Tachycardia, increased cardiac output, or arterial hypotension affect the effectiveness of VV-ECMO. One of the possible causes of hemodynamic disorders leading to ineffective VV-ECMO may be dysautonomia (DA), which refers to an imbalance of sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). The development of DA in various critical conditions was described previously. Dysautonomia also develops in COVID-19 (COVID-19-associated DA), but it was studied only in stable non-ICU patients. The presented study focuses on COVID-19-associated DA in critical COVID-19 patients requiring VV-ECMO support. The study was aimed at determining COVID-19-associated DA phenotypes, their impact on VV-ECMO effectiveness and disease outcomes. Materials and methods. The study included 20 patients: 12 (60%) females, 8 (40%) males. The patients had an average age of 55 years. All the patients underwent 24-hour Holter monitoring with spectral analysis of heart rate variability (HRV) assessing low-frequency component of the spectrum (LF), the high-frequency component of the spectrum (HF), the LF/HF ratio on days 1, 3, and 5 of VV-ECMO. Diagnostic criteria for COVID-19-associated DA was a decrease in LF/HF 2.28 or an increase in LF/HF 6.94. The diagnostic criteria of predominant tone of sympathetic nervous system (sympathetic tone) was an increase in LF/HF 6.94, while a decrease in LF/HF 2.28 indicated predominant parasympathetic tone. Low sympathetic tone was determined by a decrease in LF 15%, and an increase in LF 40%. Low parasympathetic tone was determined by a decrease in HF 15%, and an increase in HF 25%. The criteria used were based on the results of previous studies. The following parameters were registered in the study population: VV-ECMO weaning, duration of respiratory and VV-ECMO support, length of stay in the intensive care unit (ICU) and in hospital, and disease outcomes. Results. COVID-19-associated DA was diagnosed in all the patients. LF/HF median value was 0.1. HRV spectrum parameters changed significantly over time: on day 5 of VV-ECMO support LF and HF values significantly decreased. The patients were divided into three groups according to the DA phenotype: group 1 (n = 4 [20%]) with normal sympathetic tone and high parasympathetic tone (nShP phenotype); group 2 (n = 14 [70%]) with low sympathetic tone and high parasympathetic tone (lShP phenotype); group 3 (n = 2 [10%]) with low sympathetic tone and normal parasympathetic tone (lSnP phenotype). The latter group was excluded from further statistical analysis due to the small sample size. In group 2, the mean HR was significantly higher compared with group 1. In group 1, VV-ECMO weaning was successful in 50% of cases, whereas in group 2 it was successful in 7.2% (p = 0.04). Conclusions. To determine a dysautonomia phenotype, it is necessary to continuously monitor DA status in COVID-19 patients during VV-ECMO. Tachycardia in COVID-19 patients during VV-ECMO does not exclude the ANS imbalance with a significant predominance of parasympathetic tone over the sympathetic tone. It is this COVID-19-associated DA phenotype that is significantly associated with the unfavorable outcomes.

Phenotypes of COVID-19-associated dysautonomia in patients requiring veno-venous extracorporeal membrane oxygenation

Background. Patients with novel coronavirus infection (COVID-19) receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) are typically prone to hemodynamic disorders of various severity. Tachycardia, increased cardiac output, or arterial hypotension affect the effectiveness of VV-ECMO. One of the possible causes of hemodynamic disorders leading to ineffective VV-ECMO may be dysautonomia (DA), which refers to an imbalance of sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). The development of DA in various critical conditions was described previously. Dysautonomia also develops in COVID-19 (COVID-19-associated DA), but it was studied only in stable non-ICU patients. The presented study focuses on COVID-19-associated DA in critical COVID-19 patients requiring VV-ECMO support. The study was aimed at determining COVID-19-associated DA phenotypes, their impact on VV-ECMO effectiveness and disease outcomes. Materials and methods. The study included 20 patients: 12 (60%) females, 8 (40%) males. The patients had an average age of 55 years. All the patients underwent 24-hour Holter monitoring with spectral analysis of heart rate variability (HRV) assessing low-frequency component of the spectrum (LF), the high-frequency component of the spectrum (HF), the LF/HF ratio on days 1, 3, and 5 of VV-ECMO. Diagnostic criteria for COVID-19-associated DA was a decrease in LF/HF 2.28 or an increase in LF/HF 6.94. The diagnostic criteria of predominant tone of sympathetic nervous system (sympathetic tone) was an increase in LF/HF 6.94, while a decrease in LF/HF 2.28 indicated predominant parasympathetic tone. Low sympathetic tone was determined by a decrease in LF 15%, and an increase in LF 40%. Low parasympathetic tone was determined by a decrease in HF 15%, and an increase in HF 25%. The criteria used were based on the results of previous studies. The following parameters were registered in the study population: VV-ECMO weaning, duration of respiratory and VV-ECMO support, length of stay in the intensive care unit (ICU) and in hospital, and disease outcomes. Results. COVID-19-associated DA was diagnosed in all the patients. LF/HF median value was 0.1. HRV spectrum parameters changed significantly over time: on day 5 of VV-ECMO support LF and HF values significantly decreased. The patients were divided into three groups according to the DA phenotype: group 1 (n = 4 [20%]) with normal sympathetic tone and high parasympathetic tone (nShP phenotype); group 2 (n = 14 [70%]) with low sympathetic tone and high parasympathetic tone (lShP phenotype); group 3 (n = 2 [10%]) with low sympathetic tone and normal parasympathetic tone (lSnP phenotype). The latter group was excluded from further statistical analysis due to the small sample size. In group 2, the mean HR was significantly higher compared with group 1. In group 1, VV-ECMO weaning was successful in 50% of cases, whereas in group 2 it was successful in 7.2% (p = 0.04). Conclusions. To determine a dysautonomia phenotype, it is necessary to continuously monitor DA status in COVID-19 patients during VV-ECMO. Tachycardia in COVID-19 patients during VV-ECMO does not exclude the ANS imbalance with a significant predominance of parasympathetic tone over the sympathetic tone. It is this COVID-19-associated DA phenotype that is significantly associated with the unfavorable outcomes.

Applying Machine Learning Models Derived from Administrative Claims Data to Predict Medication Non-Adherence in Patients Self-Administering Biologic Medications for Inflammatory Bowel Disease

Abstract Background Adherence to self-administered biologic therapies is important to induce remission and prevent adverse clinical outcomes in inflammatory bowel disease. This study aimed to use administrative claims data and machine learning methods to predict nonadherence in an academic medical center test population. Methods A model-training dataset of beneficiaries with inflammatory bowel disease and first unique dispense of a self-administered biologic between June 30, 2016 and June 30, 2019 was extracted from the Commercial Claims and Encounters and Medicare Supplemental Administrative Claims Database. Known correlates of medication nonadherence were identified in the dataset. Nonadherence to biologic therapies was defined as a proportion of days covered ratio &amp;lt;80% at 1 year. A similar dataset was obtained from a tertiary academic medical center electronic medical record data for use in model testing. A total of 48 machine learning models were trained and assessed utilizing area under the receiver operating characteristic curve as the primary measure of predictive validity. Results The training dataset included 6,998 beneficiaries (n = 2,680 nonadherent, 38.3%) while the testing dataset included 285 patients (n = 134 nonadherent, 47.0%). When applied to test data, highest performing models had an area under the receiver operating characteristic curve of 0.55, indicating poor predictive performance. The majority of models trained had low sensitivity and high specificity. Conclusion Administrative claims-trained models were unable to predict biologic medication nonadherence in patients with inflammatory bowel disease. Future research may benefit from datasets with enriched demographic and clinical data in training predictive models.

Applying Machine Learning Models Derived from Administrative Claims Data to Predict Medication Non-Adherence in Patients Self-Administering Biologic Medications for Inflammatory Bowel Disease

Abstract Background Adherence to self-administered biologic therapies is important to induce remission and prevent adverse clinical outcomes in inflammatory bowel disease. This study aimed to use administrative claims data and machine learning methods to predict nonadherence in an academic medical center test population. Methods A model-training dataset of beneficiaries with inflammatory bowel disease and first unique dispense of a self-administered biologic between June 30, 2016 and June 30, 2019 was extracted from the Commercial Claims and Encounters and Medicare Supplemental Administrative Claims Database. Known correlates of medication nonadherence were identified in the dataset. Nonadherence to biologic therapies was defined as a proportion of days covered ratio &amp;lt;80% at 1 year. A similar dataset was obtained from a tertiary academic medical center electronic medical record data for use in model testing. A total of 48 machine learning models were trained and assessed utilizing area under the receiver operating characteristic curve as the primary measure of predictive validity. Results The training dataset included 6,998 beneficiaries (n = 2,680 nonadherent, 38.3%) while the testing dataset included 285 patients (n = 134 nonadherent, 47.0%). When applied to test data, highest performing models had an area under the receiver operating characteristic curve of 0.55, indicating poor predictive performance. The majority of models trained had low sensitivity and high specificity. Conclusion Administrative claims-trained models were unable to predict biologic medication nonadherence in patients with inflammatory bowel disease. Future research may benefit from datasets with enriched demographic and clinical data in training predictive models.

Health outcomes of electronic cigarettes.

The usage of electronic cigarettes (e-cigarettes) sparked an outbreak of unidentified vaping-related lung disease in the US during late 2019. With e-cigarettes becoming more and more popular, smokers have more options other than conventional cigarettes. Under these circumstances, a comprehensive evaluation of the general safety of new tobacco and tobacco-related products, represented by e-cigarettes, to human health is necessary. In this review, we summarize the current research on potential negative impacts of e-cigarette exposure on human health. In particular, studies detailing the relationship between e-cigarettes and the digestive system are summarized, with mechanisms mainly including hepatic metabolic dysfunction, impaired gut barrier, and worsened outcomes of inflammatory bowel disease (IBD). Although believed to be safer than traditional cigarettes, e-cigarettes exert adverse effects on systemic health and induce the development of multiple diseases containing asthma, cardiovascular disease, and IBD. Moreover, nicotine-containing e-cigarettes have a negative impact on the childhood development and increase the risk of arterial stiffness compared to the non-nicotine e-cigarettes. However, non-nicotine e-cigarette components have detrimental effects including promoting liver damage and metabolic disorders.

Multi-Omics Analysis by Machine Learning Identified Lysophosphatidic Acid as a Biomarker and Therapeutic Target for Porcine Reproductive and Respiratory Syndrome.

As a significant infectious disease in livestock, porcine reproductive and respiratory syndrome (PRRS) imposes substantial economic losses on the swine industry. Identification of diagnostic markers and therapeutic targets has been a focal challenge in PPRS prevention and control. By integrating metabolomic and lipidomic serum analyses of clinical pig cohorts through a machine learning approach with in vivo and in vitro infection models, lysophosphatidic acid (LPA) is discovered as a serum metabolic biomarker for PRRS virus (PRRSV) clinical diagnosis. PRRSV promoted LPA synthesis by upregulating the autotaxin expression, which causes innate immunosuppression by dampening the retinoic acid-inducible gene I (RIG-I) and type I interferon responses, leading to enhanced virus replication. Targeting LPA demonstrated protection against virus infection and associated disease outcomes in infected pigs, indicating that LPA is a novel antiviral target against PRRSV. This study lays a foundation for clinical prevention and control of PRRSV infections.

Multi-Omics Analysis by Machine Learning Identified Lysophosphatidic Acid as a Biomarker and Therapeutic Target for Porcine Reproductive and Respiratory Syndrome.

As a significant infectious disease in livestock, porcine reproductive and respiratory syndrome (PRRS) imposes substantial economic losses on the swine industry. Identification of diagnostic markers and therapeutic targets has been a focal challenge in PPRS prevention and control. By integrating metabolomic and lipidomic serum analyses of clinical pig cohorts through a machine learning approach with in vivo and in vitro infection models, lysophosphatidic acid (LPA) is discovered as a serum metabolic biomarker for PRRS virus (PRRSV) clinical diagnosis. PRRSV promoted LPA synthesis by upregulating the autotaxin expression, which causes innate immunosuppression by dampening the retinoic acid-inducible gene I (RIG-I) and type I interferon responses, leading to enhanced virus replication. Targeting LPA demonstrated protection against virus infection and associated disease outcomes in infected pigs, indicating that LPA is a novel antiviral target against PRRSV. This study lays a foundation for clinical prevention and control of PRRSV infections.

Managing the Intricacies of Coronary Revascularization: A Close Look at the Complete Versus Culprit-Only Approach and its Implications in Elderly Patients.

Coronary heart disease is the leading cause of mortality in the United States, and data indicates that 805,000 Americans will face a new or recurrent myocardial infarction (MI) attack every year. Frailty, a conceptual syndrome categorized by a functional decline that occurs with aging, has been linked to adverse health outcomes in cardiovascular disease and all cardiac-related procedures in general. It is therefore reasonable to deliberate that more conservative medical therapy or medical management should be considered in the frail population when managing acute coronary syndrome. This course of action has, in fact, been documented in clinical practice. However, the recent Functional Assessment in Elderly MI Patients with Multivessel Disease trial, in which all subjects were 75 years of age or above, indicated that the more invasive complete revascularization approach may be favorable over incomplete or culprit-only revascularization in patients with acute MI. In this review, we will discuss coronary heart disease and review guidelines and procedures for culprit lesion identification, including electrocardiogram procedures, coronary angiography, intravascular ultrasound, fractional flow reserve, and instantaneous fractional flow reserve. We then discuss the concept of complete vs culprit-only/incomplete coronary revascularization and staging. Following this, we will delve into recent trials discussing complete vs culprit-only revascularization, emphasizing the insights gleaned from this latest trial within this special frailty cohort which warrants special consideration.

Maintenance therapy for CTCL: importance for prevention of disease progression

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Maintenance therapy for CTCL: importance for prevention of disease progression

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Serum phosphate levels at diagnosis predict long-term risk for hypopituitarism in patients with acromegaly.

Excess growth hormone (GH) secretion in acromegaly has a major impact on mineral balance and serum phosphate levels. However, the clinical utilization of serum phosphate levels as a marker for long-term disease outcomes in acromegaly has not been evaluated. This is a retrospective study of patients with acromegaly who were followed in a tertiary center. Data were retrieved on patient characteristics, endocrine and biochemical evaluation, and tumor parameters. Comparisons were performed by measuring baseline phosphate levels and conductingcorrelation analysis and multivariable logistic regression. Sixty-one patients were followed for 4.5years (range 1-21). Patients with hyperphosphatemia (> 4.5mg/dl) at baseline had larger adenomas (15.0mm [8.0, 47.0] vs. 10.0mm [3.0, 24.0], p = 0.001), a rate chance of invasive adenoma (16 [80.0%] vs. 14 [46.7%], p = 0.02), and lower serum cortisol levels (226.0nmol/l [27.6, 516.0] vs. 294.0nmol/l [32.0, 610.0], p = 0.02). Baseline serum phosphate levels positively correlated with IGF-1 levels (r = 0.43, p = 0.003) and negatively correlated with morning plasma cortisol levels (r = -0.46, p = 0.002). Regarding long-term impact, baseline phosphate levels correlated with the number of pituitary axes involved 6months after diagnosis (r-0.34, p = 0.01). In multivariable analysis, baseline plasma phosphate levels were independently associated with risk for disease progression/recurrence (odds ratio [OR] 9.66, 95% confidence interval [CI] 1.5, 105.9, p = 0.03) and for invasive adenoma (OR 6.21, 95% CI 1.6, 28.7, p = 0.01). Elevated pretreatment serum phosphate levels are associated with a greater risk of disease persistence and recurrence and with altered pituitary function in patients with acromegaly.

Pathophysiology of hypereosinophilia-associated heart disease.

Cardiac complications in patients with hypereosinophilia cause significant morbidity and mortality. However, mechanisms of how eosinophilic inflammation causes heart damage are poorly understood. We developed a model of hypereosinophilia-associated heart disease by challenging hypereosinophilic mice with peptide from the cardiac myosin heavy chain. Disease outcomes were measured by histology, immunohistochemistry, flow cytometry, and measurement of cells and biomarkers in peripheral blood. Eosinophil dependence was determined by using eosinophil-deficient mice (ΔdblGATA). Single cells from heart were subjected to single cell RNA sequencing to assess cell composition, subtypes and expression profiles. Mice challenged with myocarditic and control peptide had peripheral blood leukocytosis, but only those challenged with myocarditic peptide had heart inflammation. Heart tissue was infiltrated by eosinophil-rich inflammatory infiltrates associated with cardiomyocyte damage. Disease penetrance and severity were dependent on the presence of eosinophils. Single cell RNA sequencing showed enrichment of myeloid cells, T-cells and granulocytes (neutrophils and eosinophils) in the myocarditic mice. Macrophages were M2 skewed, and eosinophils had an activated phenotype. Gene enrichment analysis identified several pathways potentially involved in pathophysiology of disease. Eosinophils are required for heart damage in hypereosinophilia-associated heart disease. Additionally, myeloid cells, granulocytes and T-cell cooperatively or independently participate in the pathogenesis of hypereosinophilia-associated heart disease.

An In Silico Modelling Approach to Predict Hemodynamic Outcomes in Diabetic and Hypertensive Kidney Disease.

Early diagnosis of kidney disease remains an unmet clinical challenge, preventing timely and effective intervention. Diabetes and hypertension are two main causes of kidney disease, can often appear together, and can only be distinguished by invasive biopsy. In this study, we developed a modelling approach to simulate blood velocity, volumetric flow rate, and pressure wave propagation in arterial networks of ageing, diabetic, and hypertensive virtual populations. The model was validated by comparing our predictions for pressure, volumetric flow rate and waveform-derived indexes with in vivo data on ageing populations from the literature. The model simulated the effects of kidney disease, and was calibrated to align quantitatively with in vivo data on diabetic and hypertensive nephropathy from the literature. Our study identified some potential biomarkers extracted from renal blood flow rate and flow pulsatility. For typical patient age groups, resistive index values were 0.69 (SD 0.05) and 0.74 (SD 0.02) in the early and severe stages of diabetic nephropathy, respectively. Similar trends were observed in the same stages of hypertensive nephropathy, with a range from 0.65 (SD 0.07) to 0.73 (SD 0.05), respectively. Mean renal blood flow rate through a single diseased kidney ranged from 329 (SD 40, early) to 317 (SD 38, severe) ml/min in diabetic nephropathy and 443 (SD 54, early) to 388 (SD 47, severe) ml/min in hypertensive nephropathy, showing potential as a biomarker for early diagnosis of kidney disease. This modelling approach demonstrated its potential application in informing biomarker identification and facilitating the setup of clinical trials.

Relationship between Ustekinumab trough concentrations and clinical, biochemical and endoscopic outcomes in Crohn's disease: A multi-center nationwide retrospective study (TARGET STUDY).

Ustekinumab has been shown to be effective in inducing and maintain clinical and endoscopic remission in Crohn disease (CD). We aim to assess whether ustekinumab trough levels are associated with improved outcomes in CD in real-life. We recruited patients with CD who were treated with ustekinumab for at least 6 months from January 2017 to June 2023. Patients received ustekinumab 6 mg/kg intravenous induction followed by 90 mg every 4-, 8-, or 12-weeks during maintenance were included. We assessed clinical, biochemical, and endoscopic outcomes. Trough concentrations of ustekinumab that were taken from week 42 to week 52 were measured. Primary outcome was to evaluate the relationship between ustekinumab trough concentrations and clinical remission, biochemical normalization, and endoscopic remission. Logistic regression was conducted to assess outcomes. A total of 137 patients with CD, median age of 32 years and 83 (60.6%) males. The median serum levels of ustekinumab measured was 7.2 mcg/mL (interquartile range [IQR] 3.1-9.6). Using Spearman correlation analysis, a strong negative correlation was observed between ustekinumab drug levels and simple endoscopic score (SES-CD) (r = -0.464, P < .001). Additionally, ustekinumab drug levels demonstrated substantial negative correlations with disease severity measured by Harvey-Bradshaw index (HBI) score (r = -0.582, P < .001), C-Reactive Protein (CRP) levels (r = -0.598, P < .001) and fecal calprotectin (FC) levels (r = -0.529, P < .001). A multivariable analysis adjusted for age, sex and body mass index (BMI) showed a significant association between ustekinumab serum drug levels and predefined outcomes. Ustekinumab serum drug level above 4.5 mcg/mL was associated with 24% increase in the likelihood of having an SES-CD score <3 (OR 1.24, confidence interval [CI] 1.12-1.37, P value < .001), 44% more likely to achieve HBI score <5 (OR 1.44, CI 1.26-1.65, P value < .001), 52% higher likelihood of CRP more than 10 (OR 1.52, CI 1.31-1.77, P < .001), and 42% increased likelihood of FC more than 250 (OR 1.42, CI 1.24-1.62, P < .001). Ustekinumab trough concentrations above 4.5 mcg/mL were associated with clinical, biochemical and endoscopic remission in CD. Prospective data is warranted to confirm these findings.

Analysis of Circulating Tumor DNA Predicts Outcomes of Short-Course Consolidation Immunotherapy in Unresectable Stage III NSCLC

IntroductionThe current standard of care for patients with inoperable stage III NSCLC includes chemoradiotherapy (CRT) followed by 1 year of checkpoint inhibitor (CPI) therapy. Nevertheless, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of patients with unresectable locally advanced NSCLC treated on a phase 2 trial of short-course consolidation immunotherapy after CRT, with the goal of testing whether ctDNA may be able to identify patients who do not require a full year of treatment. MethodsPlasma samples for ctDNA analysis were collected from patients on the BTCRC LUN 16-081 trial after completion of CRT, before C2D1 of CPI (i.e., 1 mo after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using CAPP-Seq. Levels of ctDNA at each time point were correlated with clinical outcomes. ResultsDetection of ctDNA predicted significantly inferior progression-free survival after completion of CRT (24-mo 29% versus 65%, p = 0.0048), before C2D1 of CPI (24-mo 0% versus 72%, p < 0.0001) and at the end of CPI (24-mo 15% versus 67%, p = 0.0011). In addition, patients with decreasing or undetectable ctDNA levels after 1 cycle of CPI had improved outcomes compared with patients with increasing ctDNA levels (24-mo progression-free survival 72% versus 0%, p < 0.0001). Progression of disease occurred within less than 12 months of starting CPI in all patients with increasing ctDNA levels at C2D1. ConclusionsDetection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment.

Cardiovascular disease risk factors in congenital heart disease survivors are associated with heart failure.

Despite advances in treatment and survival, individuals with congenital heart defects (CHD) have a higher risk of heart failure (HF) compared to the general population. To evaluate comorbidities associated with HF in patients with CHD with a goal of identifying potentially modifiable risk factors that may reduce HF-associated morbidity and mortality. Five surveillance sites in the United States linked population-based healthcare data and vital records. Individuals with an ICD-9-CM code for CHD aged 11-64 years were included and were stratified by presence of HF diagnosis code. Prevalence of death and cardiovascular risk factors based on diagnosis codes were compared by HF status using log-linear regression. A total of 25,343 individuals met inclusion/exclusion criteria. HF was documented for 2.2% of adolescents and 12.9% of adults with CHD. Adolescents and adults with HF had a higher mortality than those without HF. In both age groups, HF was positively associated with coronary artery disease, hypertension, obesity, diabetes, and increased healthcare utilization compared to those without HF. Within this population-based cohort, over 1 in 50 adolescents and 1 in 8 adults with CHD had HF, which was associated with increased mortality. Modifiable cardiovascular comorbidities were associated with HF. Five sites in the United States linked population-based healthcare data and vital records to establish surveillance network for identifying the factors which influence congenital heart disease (CHD) outcomes. Survivors of CHD frequently develop heart failure across the lifespan. Over 1 in 50 adolescent and 1 in 8 adult survivors of CHD have heart failure which is associated with increased mortality compared to CHD survivors without heart failure. Heart failure development is associated with potentially modifiable cardiovascular risk factors such as hypertension, coronary artery disease, and diabetes. Controlling modifiable cardiovascular risk factors may serve to lower the risk of heart failure and mortality in survivors of congenital heart disease of all ages.