Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P \u3c0.002), none of which achieved an AUC \u3e0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169

Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study

© 2019, American College of Rheumatology Objective: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. Methods: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti–Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy

© 2018, American College of Rheumatology Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti–tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman\u27s rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. Results: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = −0.36). Conclusion: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare

Cerebrovascular Events in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study

© 2018, American College of Rheumatology Objective: To determine the frequency, characteristics, and outcomes of cerebrovascular events (CerVEs), as well as clinical and autoantibody associations in a multiethnic/racial inception cohort of patients with systemic lupus erythematosus (SLE). Methods: A total of 1,826 patients were assessed annually for 19 neuropsychiatric (NP) events, including 5 types of CerVEs: 1) stroke, 2) transient ischemia, 3) chronic multifocal ischemia, 4) subarachnoid/intracranial hemorrhage, and 5) sinus thrombosis. Global disease activity (Systemic Lupus Erythematosus Disease [SLE] Activity Index 2000), damage scores (SLE International Collaborating Clinics/American College of Rheumatology Damage Index), and Short Form 36 (SF-36) scores were collected. Time to event, linear and logistic regressions, and multistate models were used as appropriate. Results: CerVEs were the fourth most frequent NP event: 82 of 1,826 patients had 109 events; of these events, 103 were attributed to SLE, and 44 were identified at the time of enrollment. The predominant events were stroke (60 of 109 patients) and transient ischemia (28 of 109 patients). CerVEs were associated with other NP events attributed to SLE, non–SLE-attributed NP events, African ancestry (at US SLICC sites), and increased organ damage scores. Lupus anticoagulant increased the risk of first stroke and sinus thrombosis and transient ischemic attack. Physician assessment indicated resolution or improvement in the majority of patients, but patients reported sustained reduction in SF-36 summary and subscale scores following a CerVE. Conclusion: CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician-reported outcomes, patients reported a sustained reduction in health-related quality of life following a CerVE

BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry

© 2019 Wiley Periodicals, Inc. BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide

Clinical Impact of External Laryngeal Manipulation during Laryngoscopy on Tracheal Intubation Success in Critically Ill Children

© Copyright 2017 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Objectives: External laryngeal manipulation is a commonly used maneuver to improve visualization of the glottis during tracheal intubation in children. However, the effectiveness to improve tracheal intubation attempt success rate in the nonanesthesia setting is not clear. The study objective was to evaluate the association between external laryngeal manipulation use and initial tracheal intubation attempt success in PICUs. Design: A retrospective observational study using a multicenter emergency airway quality improvement registry. Setting: Thirty-five PICUs within general and children\u27s hospitals (29 in the United States, three in Canada, one in Japan, one in Singapore, and one in New Zealand). Patients: Critically ill children (\u3c 18 years) undergoing initial tracheal intubation with direct laryngoscopy in PICUs between July 1, 2010, and December 31, 2015. Measurements and Main Results: Propensity score-matched analysis was performed to evaluate the association between external laryngeal manipulation and initial attempt success while adjusting for underlying differences in patient and clinical care factors: age, obesity, tracheal intubation indications, difficult airway features, provider training level, and neuromuscular blockade use. External laryngeal manipulation was defined as any external force to the neck during laryngoscopy. Of the 7,825 tracheal intubations, the initial tracheal intubation attempt was successful in 1,935/3,274 intubations (59%) with external laryngeal manipulation and 3,086/4,551 (68%) without external laryngeal manipulation (unadjusted odds ratio, 0.69; 95% CI, 0.62-0.75; p \u3c 0.001). In propensity score-matched analysis, external laryngeal manipulation remained associated with lower initial tracheal intubation attempt success (adjusted odds ratio, 0.93; 95% CI, 0.90-0.95; p \u3c 0.001). Conclusions: External laryngeal manipulation during direct laryngoscopy was associated with lower initial tracheal intubation attempt success in critically ill children, even after adjusting for underlying differences in patient factors and provider levels. The indiscriminate use of external laryngeal manipulation cannot be recommended