A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

INTRODUCTION: Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. METHODS: De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. RESULTS: Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. CONCLUSION: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers.

PURPOSE: The PIK3R1 gene encodes the regulatory subunit-p85a-of the PI3K signaling complex. Prior studies have found that pathogenic somatic alterations in PIK3R1 are enriched in human breast cancers but the genomic landscape of breast cancer patients harboring PIK3R1 mutations has not been extensively characterized. METHODS: We retrospectively analyzed 6,009 patient records that underwent next-generation sequencing (NGS) using the Tempus xT solid tumor assay. All patients had breast cancer with known HER2 (+/-) and hormone receptor (HR; +/-) status and were classified according to the presence of PIK3R1 mutations including short variants and copy number alterations. RESULTS: The frequency of PIK3R1 mutations varied according to subtype: 6% in triple negative (TNBC, 89/1,475), 2% in HER2-/HR+ (80/3,893) and 2.3% in HER2+ (15/641) (p < 0.001). Co-mutations in PTEN, TP53 and NF1 were significantly enriched, co-mutations in PIK3CA were significantly less prevalent, and tumor mutational burden was significantly higher in PIK3R1-mutated HER2- samples relative to PIK3R1 wild-type. At the transcriptional-level, PIK3R1 RNA expression in HER2- disease was significantly higher in PIK3R1-mutated (excluding copy number loss) samples, regardless of subtype. CONCLUSION: This is the largest investigation of the PIK3R1 mutational landscape in breast cancer patients (n = 6,009). PIK3R1 mutations were more common in triple-negative breast cancer (~ 6%) than in HER2 + or HER2-/HR + disease (approximately 2%). While alterations in the PI3K/AKT pathway are often actionable in HER2-/HR + breast cancer, our study suggests that PIK3R1 could be an important target in TNBC as well.

Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Comparing the streamlined psychotherapy "Engage" with problem-solving therapy in late-life major depression. A randomized clinical trial.

Effective psychotherapies for late-life depression are underutilized, mainly because of their complexity. "Engage" is a novel, streamlined psychotherapy that relies on neurobiology to identify core behavioral pathology of late-life depression and targets it with simple interventions, co-designed with community therapists so that they can be delivered in community settings. Consecutively recruited adults (≥60 years) with major depression (n = 249) were randomly assigned to 9 weekly sessions of "Engage" or to the evidence-based Problem-Solving Therapy (PST) offered by 35 trained community social workers and assessed by blind raters. "Engage" therapists required an average of 30% less training time to achieve fidelity to treatment than PST therapists and had one-third of the PST therapists' skill drift. Both treatments led to reduction of HAM-D scores over 9 weeks. The mixed effects model-estimated HAM-D ratings were not significantly different between the two treatments at any assessment point of the trial. The one-sided 95% CI for treatment-end difference was (-∞, 0.07) HAM-D points, indicating a non-inferiority margin of 1.3 HAM-D points or greater; this margin is lower than the pre-determined 2.2-point margin. The two treatment arms had similar response (HR = 1.08, 95% CI (0.76, 1.52), p = 0.67) and remission rates (HR = 0.89, 95% CI (0.57, 1.39), p = 0.61). We conclude that "Engage" is non-inferior to PST. If disseminated, "Engage" will increase the number of therapists who can reliably treat late-life depression and make effective psychotherapy available to large numbers of depressed older adults.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity.

BACKGROUND: Adolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT). METHODS: Retrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017. RESULTS: In 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]). CONCLUSIONS: In a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Pediatric Delirium and All-Cause PICU Readmissions Within 1 Year.

OBJECTIVES: Delirium in critically ill children is associated with increased in-hospital morbidity and mortality. Little is known about the lingering effects of pediatric delirium in survivors after hospital discharge. The primary objective of this study was to determine whether children with delirium would have a higher likelihood of all-cause PICU readmission within 1 calendar year, when compared with children without delirium. DESIGN: Retrospective cohort study. SETTING: Tertiary care, mixed PICU at an urban academic medical center. PATIENTS: Index admissions included all children admitted between September 2014 and August 2015. For each index admission, any readmission occurring within 1 year after PICU discharge was captured. INTERVENTION: Every child was screened for delirium daily throughout the PICU stay. MEASUREMENTS AND MAIN RESULTS: Among 1,145 index patients, 166 children (14.5%) were readmitted at least once. Bivariate analyses compared patients readmitted within 1 year of discharge with those not readmitted: complex chronic conditions (CCCs), increased severity of illness, longer PICU length of stay, need for mechanical ventilation, age less than 6 months, and a diagnosis of delirium were all associated with subsequent readmission. A multivariable logistic regression model was constructed to describe adjusted odds ratios for readmission. The primary exposure variable was number of delirium days. After controlling for confounders, critically ill children who experienced greater than 2 delirium days on index admission were more than twice as likely to be readmitted (adjusted odds ratio, 2.2; CI, 1.1-4.4; p = 0.023). A dose-response relationship was demonstrated as children with longer duration of delirium had increased odds of readmission. CONCLUSIONS: In this cohort, delirium duration was an independent risk factor for readmission in critically ill children. Future research is needed to determine if decreasing prevalence of delirium during hospitalization can decrease need for PICU readmission.

Long-Term Safety with Sling Mesh Implants for Stress Incontinence.

PURPOSE: We examined long-term risks and predictors of mesh erosion and reoperation following mid urethral sling procedure for stress urinary incontinence. MATERIALS AND METHODS: Women aged 18 years or older who received a mid urethral sling for stress urinary incontinence between 2008 and 2016 in outpatient surgical settings in New York State were included in our study. Those who underwent concomitant mesh pelvic organ prolapse repair were excluded. Primary outcomes were post-implantation time to erosion and reoperations. Kaplan-Meier analysis and Cox proportional hazard models were used to assess the risks of erosion diagnosis and reoperation. RESULTS: Our cohort included 36,195 women with a mean±SD age of 53.7±12.4 years. Estimated risks of erosions and reoperations at 7 years after sling procedures were 3.7% and 6.7%, respectively. Older age (≥65 vs <65: HR 0.83, 95% CI 0.70-0.99) and high volume facilities (high vs low: HR 0.79, 95% CI 0.68-0.92) were associated with a lower risk of erosion. History of hysterectomy was associated with a higher risk of erosion (HR 1.62, 95% CI 1.36-1.92). Predictors of reoperation included concurrent abdominal or native tissue transvaginal prolapse repair, previous hysterectomy and depression. CONCLUSIONS: One in 27 women had sling erosions and 1 in 15 had invasive reoperations at 7 years after sling procedures. The highest erosion cases were observed among younger White women treated at low volume facilities. Continued and vigilant surveillance of mesh in stress urinary incontinence repairs, the nature and burden of stress urinary incontinence recurrence, different types of re-treatment, patient reported outcomes and information about treating surgeons are crucial.

Quantitative Electroencephalographic Markers of Delirium in the Pediatric Intensive Care Unit: Insights From a Heterogenous Convenience Sample.

OBJECTIVE: Little is known about the underlying neurophysiology of pediatric delirium. In adult patients, the sensitivity of EEG to clinical symptoms of delirium has been noted, with a slowing of background activity (alpha) and an increase in slow-wave activity (delta-theta). In this pilot study, the authors extended this investigation to a pediatric cohort. METHODS: In a convenience sample, 23 critically ill children were screened for delirium, using the Cornell Assessment for Pediatric Delirium (CAPD), every 12 hours throughout their pediatric intensive care unit stay as part of standard intensive care unit procedure, and EEGs were performed as part of their clinical care. After hospital discharge, EEGs were reviewed using quantitative analysis, and the maximum delta-alpha ratio (DAR; eyes closed) was derived for each 12-hour period. DAR values were compared between delirious and nondelirious episodes, and the linear relationship between DAR and CAPD was assessed. RESULTS: Higher DARs were associated with episodes of delirium. The DAR also positively correlated with CAPD assessments, with higher DARs relating to higher delirium scores. CONCLUSIONS: Future prospective studies may further investigate this relationship in a more homogeneous and larger sample, and the DAR should be considered to track delirium and assess the effectiveness of therapeutic interventions.

A predictive model of clinical deterioration among hospitalized COVID-19 patients by harnessing hospital course trajectories.

From early March through mid-May 2020, the COVID-19 pandemic overwhelmed hospitals in New York City. In anticipation of ventilator shortages and limited ICU bed capacity, hospital operations prioritized the development of prognostic tools to predict clinical deterioration. However, early experience from frontline physicians observed that some patients developed unanticipated deterioration after having relatively stable periods, attesting to the uncertainty of clinical trajectories among hospitalized patients with COVID-19. Prediction tools that incorporate clinical variables at one time-point, usually on hospital presentation, are suboptimal for patients with dynamic changes and evolving clinical trajectories. Therefore, our study team developed a machine-learning algorithm to predict clinical deterioration among hospitalized COVID-19 patients by extracting clinically meaningful features from complex longitudinal laboratory and vital sign values during the early period of hospitalization with an emphasis on informative missing-ness. To incorporate the evolution of the disease and clinical practice over the course of the pandemic, we utilized a time-dependent cross-validation strategy for model development. Finally, we validated our prediction model on an external validation cohort of COVID-19 patients served in a demographically distinct population from the training cohort. The main finding of our study is the identification of risk profiles of early, late and no clinical deterioration during the course of hospitalization. While risk prediction models that include simple predictors at ED presentation and clinical judgement are able to identify any deterioration vs. no deterioration, our methodology is able to isolate a particular risk group that remain stable initially but deteriorate at a later stage of the course of hospitalization. We demonstrate the superior predictive performance with the utilization of laboratory and vital sign data during the early period of hospitalization compared to the utilization of data at presentation alone. Our results will allow efficient hospital resource allocation and will motivate research in understanding the late deterioration risk group.

Assessment of provider practices regarding venous thromboembolism management and prevention in pediatric acute leukemia patients.

Despite the known occurrence of venous thromboembolism (VTE) in the pediatric oncology population, there are no leukemia-specific VTE treatment guidelines. The primary objective of this study was to assess current practices regarding the management and prevention of VTE in the pediatric acute lymphoblastic leukemia (ALL) population. We performed a cross sectional, anonymous, electronic survey of members of the American Society of Hematology and the pediatric subcommittee of VENUS (VTE Network US of the Hemostasis and Thrombosis Research Society). Survey items included questions on demographics and clinical practice. Of 870 surveys distributed, 154 were submitted, giving a 17.7% response rate. Treatment duration, re-imaging timeline, and class of anticoagulants used were reported for catheter-associated deep vein thrombus, pulmonary embolism, and cerebral venous sinus thrombosis. While there are some common themes regarding VTE management, there is notable variation in the overall practice as well as with the decision to continue anticoagulation in the presence of thrombocytopenia. Given the variation seen, a multi-center, prospective clinical trial is urgently needed for developing consensus guidelines for the management of VTE in children with ALL.

Early Use of Antiseizure Medication in Mechanically Ventilated Traumatic Brain Injury Cases: A Retrospective Pediatric Health Information System Database Study.

OBJECTIVES: Traumatic brain injury is a leading cause of morbidity and mortality in children. Post-traumatic seizures occur in 25% of children with severe traumatic brain injury and may worsen outcomes. Our objective was to use a retrospective cohort study to examine the association between the early seizure occurrence and the choice of early antiseizure medication in children with traumatic brain injury. DESIGN: Retrospective cohort study using the Pediatric Health Information Systems database, 2010-2017. SETTING: Fifty-one U.S. children's hospitals. PATIENTS: Children (< 18 yr old at admission) with diagnostic codes for traumatic brain injury who were mechanically ventilated at the time of admission and with hospital length of stay greater than 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3,479 children were identified via coding and including in the analysis. Patients receiving antiseizure medication starting day 0 with levetiracetam were compared with those receiving phenytoin. The outcome was seizure occurrence, identified using validated International Classification of Diseases, 9th Revision, Clinical Modification and International Classification of Diseases, 10th Revision, Clinical Modification diagnosis codes. The median (interquartile range) age of patients was 4 (1-11) years, and the most common mechanism of injury was motor vehicle accident, occurring in 960 of patients (27%). A total of 2,342 patients (67%) received levetiracetam on day 0 and 1,137 patients (33%) received phenytoin on day 0. Totally 875 patients (37%) receiving levetiracetam on day 0 developed seizures, compared with 471 patients (41%) receiving phenytoin on day 0 (p = 0.02). Upon multivariable analysis adjusting for age, injury by child abuse, subdural hemorrhage, ethnicity, and admission year, children receiving phenytoin on day 0 were 1.26 (95% CI, 1.07-1.48) times more likely to be associated with post-traumatic seizure occurrence, compared with children receiving levetiracetam on day 0 (p = 0.01). CONCLUSIONS: Early administration of levetiracetam was associated with less-frequent seizure occurrence than early administration of phenytoin in mechanically ventilated children with traumatic brain injury. Additional studies are necessary to determine if the association is causal or due to unmeasured confounders and/or selection bias.

Chronic pain diagnosis in refugee torture survivors: A prospective, blinded diagnostic accuracy study.

BACKGROUND: An estimated 87% of torture survivors experience chronic pain such as brachial plexopathy from upper extremity suspension or lumbosacral plexus injury from leg hyperextension. However, a vast majority of pain is undetected by evaluators due to a lack of diagnostic tools and confounding psychiatric illness. This diagnostic gap results in exclusive psychological treatment rather than multimodal therapies, substantially limiting rehabilitation. We hypothesized that the United Nations Istanbul Protocol (UNIP) would have a sensitivity of approximately 15% for pain detection, and that the use of a validated pain screen would improve its sensitivity by at least 29%, as compared to the reference standard (pain specialist evaluation). METHODS AND FINDINGS: This prospective blind-comparison-to-gold-standard study of survivors of torture, as defined by the World Medical Association, took place at Weill Cornell Medicine between February 1, 2017, and June 21, 2019. 11 women and 9 men, for a total of 20 participants, were included in the analysis. Five participants received 2 UNIP evaluations, for a total of 25 unique evaluations included in the analysis. Participants were representative of a global population, with home countries in Africa, Central America, South Asia, the Caribbean, and the Middle East. Methods of torture experienced were homogeneous, following the predictable pattern of systematic torture. Participants first received the standard evaluation protocol for torture survivors (UNIP) by a trained evaluator, and subsequently received a validated pain screen (Brief Pain Inventory-Short Form [BPISF]) followed by a noninvasive examination by a pain specialist physician (reference standard). The primary outcome was the diagnostic and treatment capability of the standard protocol (index test) versus the validated pain screen (BPISF), as compared to the reference standard. Trained evaluators performing the initial assessment with the UNIP (index test) were blinded to the study, and the pain specialist physician (reference standard) was blinded to the outcome of the initial UNIP evaluation and the BPISF; data from the initial UNIP assessment were not gathered by the principal investigator until all other study procedures were completed. Providers using only the UNIP captured pain in a maximum of 16% of evaluations, as compared to 85% of participants being diagnosed with pain by the reference standard. When employed, the validated pain screen had a sensitivity of 100% (95% CI 72%-100%) and a negative predictive value of 100%, as compared to a sensitivity of 24% (95% CI 8%-50%) and a negative predictive value of 19% (95% CI 5%-46%) for the index test. The difference in the sensitivity of the UNIP as compared to the BPISF was significant, with p < 0.001. No adverse events owing to participation in the study were reported by participants. Limitations of the study include small sample size, its single-site nature, and the exclusion of individuals who did not speak 1 of the 5 study languages. CONCLUSIONS: These data indicate that a validated pain screen can supplement the current global standard assessment of torture survivors, the UNIP, to increase the accuracy of pain diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03018782.

Association Between Pediatric Delirium and Quality of Life After Discharge.

OBJECTIVE: Delirium occurs frequently in critically ill children, with highest rates reported in children under 5 years old. The objective of this study was to measure the residual effect of delirium on quality of life at 1 and 3 months after hospital discharge. DESIGN: Prospective observational cohort study. SETTING: Urban academic PICU. PATIENTS: Children younger than five years of age at time of admission to the PICU. INTERVENTIONS: All children were screened for delirium (using the Cornell Assessment for Pediatric Delirium) throughout their stay in the PICU. Quality of life was measured using the Infant-Toddler Quality of Life questionnaire at three time points: baseline, 1 month, and 3 months after hospital discharge. Infant-Toddler Quality of Life scores were compared between children who did and did not develop delirium. MEASUREMENTS AND MAIN RESULTS: Two hundred seven children were enrolled. One hundred twenty-two completed the 1-month follow-up, and 117 completed the 3-month follow-up. Fifty-six children (27%) developed delirium during their PICU stay. At follow-up, Infant-Toddler Quality of Life scores for the PICU cohort overall were consistently lower than age-related norms. When analyzed by delirium status, children who had experienced delirium scored lower in every quality of life domain when compared with children who did not experience delirium. Even after controlling for severity of illness, delirious patients demonstrated an average 11-point lower general health score than nondelirious patients (p = 0.029). CONCLUSION: This pilot study shows an independent association between delirium and decreased quality of life after hospital discharge in young children.

Black/African American Patients with Pediatric Crohn's Disease Report Less Anxiety and Fatigue than White Patients.

OBJECTIVES: To compare patient-reported outcomes in black/African American patients with white patients participating in IBD Partners Kids & Teens, in order to identify possible racial healthcare disparities in pediatric inflammatory bowel disease (IBD) as future targets for improvement. STUDY DESIGN: This was a cross-sectional analysis comparing patient-reported outcomes in black/African American patients with white patients, aged 9-18 years, with IBD participating in the IBD Partners Kids & Teens cohort from August 2013 to April 2018. Secondary outcomes included number of IBD-related hospitalizations and surgeries, current medication use, and disease activity. RESULTS: We included 401 patients with Crohn's disease (white = 378 [94%]; black/African American = 23 [6%]). For children with Crohn's disease, black/African American patients compared with white patients reported less anxiety (40.7 vs 47.5, P = .001) and fatigue (44.3 vs 48.4, P = .047) despite more frequently reported treatment with biologics (91% vs 61%, P = .006) and antibiotics (17% vs 5%, P = .03) and history of hospitalizations (81% vs 52%, P = .02). CONCLUSIONS: Black/African American children with Crohn's disease were less likely to report anxiety or fatigue than white patients, despite an apparent more severe disease course reflected by greater reported frequency of treatment with biologics and antibiotics and history of hospitalizations.

Anxiety and Type 1 Diabetes Management: Guardian and Child Report in a Pediatric Endocrinology Clinic.

BACKGROUND: Childhood anxiety prevents optimal diabetes management yet may be underrecognized by guardians. OBJECTIVE: We aimed to investigate associations among anxiety, diabetes treatment adherence, and diabetes symptom control through child and guardian report. METHODS: Cross-sectional pilot study surveying a convenience sample of children (ages 2-21) in a pediatric endocrinology clinic. Behavior Assessment System for Children, Second Edition 2, Self-Care Inventory Report, and Pediatric Quality of Life measured anxiety, diabetes treatment adherence, and diabetes symptom control. Analyses were performed with Spearman correlations. RESULTS: Prevalence of anxiety and related behaviors was higher when reported by children (13% and 24%) vs. guardians (5% and 13%). Child-reported anxiety was associated with worse symptom control in all ages (Pediatric Quality of Life [rs = -0.55, P < 0.01]) and worse treatment adherence in children aged ≤12 (Self-Care Inventory Report [rho = -0.601, P = 0.023]). Guardian-reported anxiety was associated with worse symptom control (Peds QL [rs = -0.38, P = 0.02]). Child- and guardian-reported anxiety were positively correlated (rho = 0.426, P = 0.017)-particularly for children aged >12 (rho = 0.686, P = 0.003)-although not significantly for children ≤ 12 (rho = 0.201, P = 0.473). CONCLUSION: Anxiety in children with type 1 diabetes varies with the domain of diabetes management (treatment adherence vs. symptom control) and reporting source (child vs. guardian). Children aged ≤12 exhibited a stronger relationship between higher anxiety and worse diabetes management with worse treatment adherence and symptom control in the presence of higher anxiety. Guardians of younger children were less effective at recognizing symptoms. Challenges identifying anxiety and its detrimental effects on diabetes management suggest routine screening of anxiety in pediatric endocrinology clinics is especially salient.

C-Reactive Protein and Procalcitonin Levels May Not Predict Delirium in Critically Ill Children.

OBJECTIVES: The objective of this study was to investigate the relationship between C-reactive protein and procalcitonin and the diagnosis of delirium in critically ill children. DESIGN: Retrospective cohort study. SETTING: Tertiary care urban academic PICU. PATIENTS: All PICU patients (ages 0-21 yr) admitted between January 1, 2015, and December 31, 2017, who had a C-reactive protein and/or procalcitonin level drawn within the first 14 days of their PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Each patient was screened for delirium and/or coma bid using the Cornell Assessment of Pediatric Delirium. Patient information including demographics, delirium status, and laboratory values were extracted from the electronic medical record. Seven-hundred thirty-four patients were enrolled, with C-reactive protein and procalcitonin levels drawn in 664 and 587 patients, respectively. Thirty-seven percent of patients (n = 274) were delirious on at least one study day. In bivariate analysis, C-reactive protein was not related to either delirium or coma. Procalcitonin was highest on days with coma and lowest on days with delirium. There was no statistically significant relationship between inflammatory markers and any subtype of delirium. CONCLUSIONS: Despite evidence of inflammatory markers being predictive of delirium in adults, in this retrospective pediatric cohort, no association was found between C-reactive protein or procalcitonin levels and development of delirium.

Delirium and Developmental Disability: Improving Specificity of a Pediatric Delirium Screen.

OBJECTIVES: Children with developmental disabilities are at high risk for developing delirium when critically ill. However, existing pediatric delirium screening tools were designed for children with typical development. The objective of this study was to improve the specificity of the Cornell Assessment for Pediatric Delirium, to allow for accurate detection of delirium in developmentally delayed children admitted to the PICU. We hypothesized that the Cornell Assessment for Pediatric Delirium, when combined with fluctuation in level of awareness as measured by the Richmond Agitation-Sedation Scale, would be valid and reliable for the diagnosis of delirium in developmentally delayed children. DESIGN: Prospective observational double-blind cohort study. SETTING: Tertiary care academic PICU. PATIENTS: Children with moderate to severe developmental delay. INTERVENTIONS: Each child was evaluated by the bedside nurse with the Cornell Assessment for Pediatric Delirium once every 12 hours and the Richmond Agitation-Sedation Scale every 4 hours. Cornell Assessment for Pediatric Delirium (score ≥ 9) + Richmond Agitation-Sedation Scale fluctuation (change in Richmond Agitation-Sedation Scale score of at least 2 points during a 24-hr period) was compared with the criterion standard psychiatric evaluation for diagnosis of delirium. MEASUREMENTS AND MAIN RESULTS: Forty children participated; 94 independent paired assessments were completed. The psychiatrists' diagnostic evaluations were compared with the detection of delirium by the Cornell Assessment for Pediatric Delirium and Richmond Agitation-Sedation Scale. Specificity of the Cornell Assessment for Pediatric Delirium + Richmond Agitation-Sedation Scale fluctuation was 97% (CI, 90-100%), positive predictive value of Cornell Assessment for Pediatric Delirium + Richmond Agitation-Sedation Scale fluctuation was 89% (CI, 65-99%); and negative predictive value remained acceptable at 87% (95% CI, 77-94%). In addition, to confirm interrater reliability of the criterion standard, 11 assessments were performed by two or more psychiatrists in a blinded fashion. There was perfect agreement (κ = 1), indicating reliability in psychiatric diagnosis of delirium in developmentally delayed children. CONCLUSION: When used in conjunction with Richmond Agitation-Sedation Scale score fluctuation, the Cornell Assessment for Pediatric Delirium is a sensitive and specific tool for the detection of delirium in children with developmental delay. This allows for reliable delirium screening in this hard-to-assess population.

Two- or 3-Dimensional Echocardiography-Derived Cardiac Output Cannot Replace the Pulmonary Artery Catheter in Cardiac Surgery.

OBJECTIVES: Three-dimensional (3D) transesophageal echocardiography (TEE) has been shown to be more accurate than 2D TEE for the evaluation of the left ventricular outflow tract area. The aim of the present study was to compare the agreement of 3D echocardiography-derived cardiac output (CO) with thermodilution-derived CO (TDCO) before and after cardiopulmonary bypass (CPB). DESIGN: This was a prospective observational study of patients who underwent cardiac surgery between 2016 and 2018. SETTING: Weill Cornell Medicine, a single large academic medical center. PARTICIPANTS: The study comprised 78 patients undergoing elective cardiac surgery. INTERVENTIONS: CPB, TEE, pulmonary artery catheter, and elective cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Two-dimensional CO, 3D CO-diameter, and 3D CO-area values pre-CPB were strongly correlated with one another both pre-CPB and post-CPB. The 3D CO-diameter and the 3D CO-area were mildly correlated, with TDCO measurements pre-CPB (r = 0.46 and 0.39, respectively) and post-CBP (r = 0.43 and 0.47, respectively). Pre-CPB 3D CO-diameter had the most agreement with TDCO in terms of bias (-0.13 L/min); however, the limits of agreement (LOA) were wide (-2.2- to- 2.45 L/min). Post-CPB, 3D CO-diameter had the most agreement with TDCO in terms of bias (0.41) but with wide LOA (-3.29 to 2.47). All pre-CPB echocardiography-derived CO (2D CO, 3D CO-diameter, 3D CO-area) had more agreement with TDCO than did post-CPB measurements. CONCLUSIONS: Three-dimensional CO measurements were only modestly correlated with pulmonary artery catheter-derived CO pre-bypass and post-bypass. Despite low bias, the wide LOA from 2D CO, 3D CO-diameter, and 3D-area compared with TDCO suggested that the 2 methods are not interchangeable.

Use of Pulmonary Artery Pulsatility Index in Cardiac Surgery.

OBJECTIVE: This study evaluated whether the pulmonary artery pulsatility index (PAPi) collected before and after cardiopulmonary bypass (CPB) is predictive and diagnostic of new onset right ventricular (RV) failure in the elective cardiac surgical population. DESIGN: This was a prospective observational study of patients who underwent cardiac surgery between 2017 and 2019. SETTING: Weill Cornell Medicine, a single large academic medical center. PARTICIPANTS: The study comprised 119 patients undergoing elective cardiac surgery. INTERVENTIONS: Cardiopulmonary bypass, transesophageal echocardiography, pulmonary artery catheter, and elective cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Echocardiographic and hemodynamic data were collected at 2 time points: pre-CPB and post-chest closure/post-CPB. Patients with and without post-CPB RV dysfunction fractional area of change (<35%) were compared, and receiver operating characteristic curves were constructed. One hundred and nineteen patients undergoing elective surgery-coronary artery bypass grafting (23%), aortic valve replacement (21%), aortic surgery (19%), and combined surgery (37%)-were evaluated. Post-CPB RV dysfunction was associated with lower pre-CPB PAPi values (2.0 ± 1.0 v 2.5 ± 1.2; p = 0.001 and p = 0.03) and higher pre-CPB central venous pressure (8.3 ± 3.6 and 6.9 ± 2.7; p = 0.003 and p = 0.02, respectively). Pre-CPB PAPi (0.98 [95% confidence interval {CI} 0.96-0.99]), end systolic area (0.99 [95% CI 0.98-0.99]), and end diastolic area (1.01 [95% CI 1.001-1.02]) were independently associated with RV dysfunction in multivariable modeling, with a lower PAPi and end systolic area and higher end diastolic area demonstrating a greater risk of RV dysfunction post-CPB (post-CPB area under the curve for PAPi 0.80 [95% CI 0.71-0.88; sensitivity = 0.68, specificity = 0.93, optimal cutoff = 1.9]). CONCLUSIONS: PAPi measured pre-CPB is a potential predictor and marker of post-CPB RV dysfunction and may have diagnostic utility in cardiac surgery. Additional, large-scale studies are needed to confirm this finding.

The impact of food order on postprandial glycaemic excursions in prediabetes.

Data suggest that nutrient order during a meal significantly impacts postprandial glucose and insulin excursions in type 2 diabetes, while its effects in prediabetes have not been reported. Fifteen participants with prediabetes consumed the same meal on 3 days in random order: carbohydrate first, followed 10 minutes later by protein and vegetables (CF); protein and vegetables first, followed 10 minutes later by carbohydrate (PVF); or vegetables first followed by protein and carbohydrate (VF). Blood was sampled for glucose and insulin measurements at 0, 30, 60, 90, 120, 150 and 180 minutes. Incremental glucose peaks were similarly attenuated by >40% in the PVF and VF meal conditions compared with CF. The incremental area under the curve for glucose was 38.8% lower following the PVF meal order, compared with CF, and postprandial insulin excursions were significantly lower in the VF meal condition compared with CF. The CF meal pattern showed marked glycaemic variability whereas glucose levels were stable in the PVF and VF meal conditions. Food order presents a novel, simple behavioural strategy to reduce glycaemic excursions in prediabetes.