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Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial.
Weiss EM, Olszewski AE, Guttmann KF, Magnus BE, Li S, Shah AR, Juul SE, Wu YW, Ahmad KA, Bendel-Stenzel E, Isaza NA, Lampland AL, Mathur AM, Rao R, Riley D, Russell DG, Salih ZNI, Torr CB, Weitkamp JH, Anani UE, Chang T, Dudley J, Flibotte J, Havrilla EM, Kathen CM, O'Kane AC, Perez K, Stanley BJ, Wilfond BS, Shah SK
(2021) JAMA Netw Open 4: e2032106
MeSH Terms: Biomedical Research, Clinical Trials as Topic, Female, Humans, Infant, Newborn, Male, Parental Consent, Parents, Refusal to Participate, Surveys and Questionnaires, Trust
Show Abstract · Added April 16, 2021
Importance - It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.
Objective - To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.
Design, Setting, and Participants - This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020.
Exposure - Parental choice of enrollment in neonatal clinical trial.
Main Outcomes and Measures - Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers.
Results - Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment.
Conclusions and Relevance - In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.
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Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Pietzner M, Wheeler E, Carrasco-Zanini J, Raffler J, Kerrison ND, Oerton E, Auyeung VPW, Luan J, Finan C, Casas JP, Ostroff R, Williams SA, Kastenmüller G, Ralser M, Gamazon ER, Wareham NJ, Hingorani AD, Langenberg C
(2020) Nat Commun 11: 6397
MeSH Terms: ABO Blood-Group System, Aptamers, Peptide, Blood Coagulation, COVID-19, Drug Delivery Systems, Female, Gene Expression Regulation, Host-Derived Cellular Factors, Host-Pathogen Interactions, Humans, Internet, Male, Middle Aged, Proteins, Quantitative Trait Loci, SARS-CoV-2
Show Abstract · Added December 18, 2020
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
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16 MeSH Terms
Arterial Thrombotic Complications of Tyrosine Kinase Inhibitors.
Wu MD, Moslehi JJ, Lindner JR
(2021) Arterioscler Thromb Vasc Biol 41: 3-10
MeSH Terms: Animals, Antineoplastic Agents, Arterial Occlusive Diseases, Humans, Molecular Targeted Therapy, Neoplasms, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Risk Assessment, Risk Factors, Thrombosis
Show Abstract · Added January 23, 2021
Abnormal expression or function of several classes of kinases contribute to the development of many types of solid and hematologic malignancies. TKs (tyrosine kinases) in particular play a role in tumor growth, metastasis, neovascularization, suppression of immune surveillance, and drug resistance. TKIs (tyrosine kinase inhibitors) targeted to TKs such as BCR-ABL1, VEGF receptors, PDGF receptors, have transformed therapy of certain forms of cancer by providing excellent efficacy with relatively low adverse event rates. Yet some of these agents have been associated with high rates of vascular events, presumably from prothrombotic complications that result in myocardial infarction, stroke, and critical limb ischemia. This review describes the scope of the problem evidenced by clinical experience with some of the most commonly used TKIs, with a focus on TKIs targeted to the BCR-ABL1 (breakpoint cluster region-Abelson 1) translocation. We also discuss the potential mechanisms responsible for arterial thrombotic complications that could lead to mitigation strategies or unique TK targeting strategies to reduce adverse event rates without compromising efficacy.
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COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pandemic's Impact in Type 1 and Type 2 Diabetes.
Gregory JM, Slaughter JC, Duffus SH, Smith TJ, LeStourgeon LM, Jaser SS, McCoy AB, Luther JM, Giovannetti ER, Boeder S, Pettus JH, Moore DJ
(2021) Diabetes Care 44: 526-532
MeSH Terms: COVID-19, Comorbidity, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Electronic Health Records, Female, Hospitalization, Humans, Hypertension, Male, Middle Aged, Odds Ratio, Prospective Studies, Severity of Illness Index
Show Abstract · Added December 7, 2020
OBJECTIVE - To quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)-related hospitalization and illness severity in type 1 diabetes.
RESEARCH DESIGN AND METHODS - We conducted a prospective cohort study to identify case subjects with COVID-19 across a regional health care network of 137 service locations. Using an electronic health record query, chart review, and patient contact, we identified clinical factors influencing illness severity.
RESULTS - We identified COVID-19 in 6,138, 40, and 273 patients without diabetes and with type 1 and type 2 diabetes, respectively. Compared with not having diabetes, people with type 1 diabetes had adjusted odds ratios of 3.90 (95% CI 1.75-8.69) for hospitalization and 3.35 (95% CI 1.53-7.33) for greater illness severity, which was similar to risk in type 2 diabetes. Among patients with type 1 diabetes, glycosylated hemoglobin (HbA), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity.
CONCLUSIONS - Diabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA) had significant but modest impact compared with comparatively static factors (e.g., race and insurance) in type 1 diabetes, indicating an urgent and continued need to mitigate severe acute respiratory syndrome coronavirus 2 infection risk in this community.
© 2020 by the American Diabetes Association.
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Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.
Ammirati E, Frigerio M, Adler ED, Basso C, Birnie DH, Brambatti M, Friedrich MG, Klingel K, Lehtonen J, Moslehi JJ, Pedrotti P, Rimoldi OE, Schultheiss HP, Tschöpe C, Cooper LT, Camici PG
(2020) Circ Heart Fail 13: e007405
MeSH Terms: Acute Disease, Cardiology, Chronic Disease, Consensus, Humans, Myocarditis, Predictive Value of Tests, Risk Factors, Terminology as Topic, Treatment Outcome
Show Abstract · Added January 23, 2021
Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.
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Clear cell renal cell carcinoma ontogeny and mechanisms of lethality.
Jonasch E, Walker CL, Rathmell WK
(2021) Nat Rev Nephrol 17: 245-261
MeSH Terms: Biomarkers, Tumor, Carcinoma, Renal Cell, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Mutation, Prognosis, Tumor Microenvironment
Show Abstract · Added April 27, 2021
The molecular features that define clear cell renal cell carcinoma (ccRCC) initiation and progression are being increasingly defined. The TRACERx Renal studies and others that have described the interaction between tumour genomics and remodelling of the tumour microenvironment provide important new insights into the molecular drivers underlying ccRCC ontogeny and progression. Our understanding of common genomic and chromosomal copy number abnormalities in ccRCC, including chromosome 3p loss, provides a mechanistic framework with which to organize these abnormalities into those that drive tumour initiation events, those that drive tumour progression and those that confer lethality. Truncal mutations in ccRCC, including those in VHL, SET2, PBRM1 and BAP1, may engender genomic instability and promote defects in DNA repair pathways. The molecular features that arise from these defects enable categorization of ccRCC into clinically and therapeutically relevant subtypes. Consideration of the interaction of these subtypes with the tumour microenvironment reveals that specific mutations seem to modulate immune cell populations in ccRCC tumours. These findings present opportunities for disease prevention, early detection, prognostication and treatment.
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Patent Ductus Arteriosus of the Preterm Infant.
Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, Hansmann G
(2020) Pediatrics 146:
MeSH Terms: Algorithms, Ductus Arteriosus, Patent, Humans, Infant, Newborn, Infant, Premature
Show Abstract · Added January 7, 2021
Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.
Copyright © 2020 by the American Academy of Pediatrics.
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Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial.
Cummings JJ, Gerday E, Minton S, Katheria A, Albert G, Flores-Torres J, Famuyide M, Lampland A, Guthrie S, Kuehn D, Weitkamp JH, Fort P, Abu Jawdeh EG, Ryan RM, Martin GC, Swanson JR, Mulrooney N, Eyal F, Gerstmann D, Kumar P, Wilding GE, Egan EA, AERO-02 STUDY INVESTIGATORS
(2020) Pediatrics 146:
MeSH Terms: Administration, Oral, Aerosols, Biological Products, Cohort Studies, Female, Gestational Age, Humans, Infant, Newborn, Intensive Care Units, Neonatal, Intubation, Intratracheal, Male, Nebulizers and Vaporizers, Prospective Studies, Pulmonary Surfactants, Respiratory Distress Syndrome, Newborn
Show Abstract · Added April 16, 2021
BACKGROUND - Exogenous surfactants to treat respiratory distress syndrome (RDS) are approved for tracheal instillation only; this requires intubation, often followed by positive pressure ventilation to promote distribution. Aerosol delivery offers a safer alternative, but clinical studies have had mixed results. We hypothesized that efficient aerosolization of a surfactant with low viscosity, early in the course of RDS, could reduce the need for intubation and instillation of liquid surfactant.
METHODS - A prospective, multicenter, randomized, unblinded comparison trial of aerosolized calfactant (Infasurf) in newborns with signs of RDS that required noninvasive respiratory support. Calfactant was aerosolized by using a Solarys nebulizer modified with a pacifier adapter; 6 mL/kg (210 mg phospholipid/kg body weight) were delivered directly into the mouth. Infants in the aerosol group received up to 3 treatments, at least 4 hours apart. Infants in the control group received usual care, determined by providers. Infants were intubated and given instilled surfactant for persistent or worsening respiratory distress, at their providers' discretion.
RESULTS - Among 22 NICUs, 457 infants were enrolled; gestation 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The rates of intubation for surfactant instillation were 26% in the aerosol group and 50% in the usual care group ( < .0001). Respiratory outcomes up to 28 days of age were no different.
CONCLUSIONS - In newborns with early, mild to moderate respiratory distress, aerosolized calfactant at a dose of 210 mg phospholipid/kg body weight reduced intubation and surfactant instillation by nearly one-half.
Copyright © 2020 by the American Academy of Pediatrics.
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Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer.
Hoover AA, Hufnagel DH, Harris W, Bullock K, Glass EB, Liu E, Barham W, Crispens MA, Khabele D, Giorgio TD, Wilson AJ, Yull FE
(2020) BMC Cancer 20: 970
MeSH Terms: Animals, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Humans, Macrophages, Mice, Mice, Transgenic, NF-kappa B, Signal Transduction
Show Abstract · Added January 29, 2021
BACKGROUND - New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-κB activity in immunocompetent mouse models of ovarian cancer.
METHODS - We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-κB activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value < 0.05 was considered statistically significant.
RESULTS - Increased expression of the cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox) administration, demonstrated greater necrosis and immune infiltration than control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in macrophage populations away from the M2 and towards the anti-tumor M1 phenotype. There were also increased tumor-infiltrating CD3/CD8 T cells in IKFM mice, accompanied by higher levels of CXCL9, a T cell activating factor secreted by macrophages, in IKFM ascitic fluid.
CONCLUSIONS - In syngeneic ovarian cancer models, increased canonical NF-κB signaling in macrophages promoted anti-tumor TAM phenotypes and increased cytotoxic T cell infiltration, which was sufficient to limit tumor progression. This may present a novel translational approach for ovarian cancer treatment, with the potential to increase responses to T cell-directed therapy in future studies.
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A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.
Zhou D, Jiang Y, Zhong X, Cox NJ, Liu C, Gamazon ER
(2020) Nat Genet 52: 1239-1246
MeSH Terms: Animals, Gene Expression Profiling, Genetic Association Studies, Humans, Lipoproteins, LDL, Mendelian Randomization Analysis, Mice, Models, Genetic, Multifactorial Inheritance, Predictive Value of Tests
Show Abstract · Added October 7, 2020
Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.
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10 MeSH Terms