Screening for Hypertension in adolescents living with HIV: Protocol for a cluster randomized trial to improve guideline adherence.

BACKGROUND: Although AIDS-related deaths have reduced with increased access to antiretroviral care, cardiovascular disease-related morbidities among persons living with HIV are rising. Contributing to this is the higher incidence of Hypertension among Persons Living with HIV. The duration of exposure to the virus and antiretroviral drugs plays a vital role in the pathogenesis, putting perinatally infected children and adolescents at higher risk than behaviorally-infected ones, supporting the calls for increased surveillance of Hypertension among them. Despite the availability of guidelines to support this surveillance, the blood pressure (BP) of adolescents living with HIV (ADLHIV) is not checked during clinical visits. This study aims to assess the effect of a theory-based intervention on healthcare workers' adherence to the guidelines for hypertension screening among adolescents. METHODS: A multi-facility cluster-randomized study will be conducted. The clusters will be 20 antiretroviral therapy sites in the Greater Accra Region of Ghana with the highest adolescent caseload. Data will be extracted from the folders of adolescents (10-17 years) who received care in these facilities six months before the study. The ART staff of intervention facilities will receive a multicomponent theory of planned behaviour-based intervention. This will include orientation on hypertension risk among ADLHIV, provision of job aids and pediatric sphygmomanometers. Six months after the intervention, the outcome measure will be the change from baseline in the proportion of ADLHIV whose BP was checked during clinical visits. The calculated sample size is 400 folders. IMPLICATIONS OF FINDINGS: This study will generate evidence on the effectiveness of a multicomponent theory-based intervention for improving the implementation of clinical practice guidelines. TRIAL REGISTRATION: PACTR202205641023383.

Parent Priorities in End-of-Life Care for Children With Cancer.

Importance: Robust quality measures to benchmark end-of-life care for children with cancer do not currently exist; 28 candidate patient-centered quality measures were previously developed. Objective: To prioritize quality measures among parents who lost a child to cancer. Design, Setting, and Participants: This survey study was conducted using an electronic, cross-sectional discrete choice experiment (DCE) with maximum difference scaling from January to June 2021 in the US. In each of 21 questions in the DCE, participants were presented with a set of 4 quality measures and were asked to select the most and least important measures within each set. All 28 quality measures were presented an equal number of times in different permutations. In the volunteer sample, 69 eligible bereaved parents enrolled in the study; 61 parents completed the DCE (participation rate, 88.4%). Main Outcomes and Measures: Using choices participants made, a hierarchical bayesian multinomial logistic regression was fit to derive mean importance scores with 95% credible intervals (95% Crs) for each quality measure, representing the overall probability of a quality measure being selected as most important. Importance scores were rescaled proportionally from 0 to 100, with the sum of scores for all quality measures adding up to 100. This enabled interpretation of scores as the relative importance of quality measures. Results: Participants included 61 bereaved parents (median [range] age, 48 [24-74] years; 55 individuals self-identified as women [90.2%]; 1 American Indian or Alaska Native [1.6%], 1 Asian [1.6%], 2 Black or African American [3.3%], 1 Native Hawaiian or Pacific Islander, and 58 White [91.8%]; 58 not Hispanic or Latinx [95.1%]). Highest-priority quality measures by mean importance score included having a child's symptoms treated well (9.25 [95% Cr, 9.06-9.45]), feeling that a child's needs were heard by the health care team (8.39 [95% Cr, 8.05-8.73]), and having a goal-concordant end-of-life experience (7.45 [95% Cr, 6.84-8.05]). Lowest-priority quality measures included avoiding chemotherapy (0.33 [95% Cr, 0.21-0.45]), provision of psychosocial support for parents (1.01 [95% Cr, 0.57-1.45]), and avoiding the intensive care unit (1.09 [95% Cr, 0.74-1.43]). Rank-ordering measures by mean importance revealed that symptom management was 9 times more important to parents than psychosocial support for themselves. Conclusions and Relevance: This study found that bereaved parents prioritized end-of-life quality measures focused on symptom management and goal-concordant care while characterizing quality measures assessing their own psychosocial support and their child's hospital resource use as substantially less important. These findings suggest that future research should explore innovative strategies to measure care attributes that matter most to families of children with advanced cancer.

Impact of school-supervised ultra-long-acting basal insulin injections on ketosis in youth with T1D and elevated haemoglobin A1c: A pilot study.

BACKGROUND: In youth with type 1 diabetes (T1D), high haemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA). AIMS: This study examined whether daily school-supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections. MATERIALS & METHODS: After a 2-4-week run-in, youth (10-18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school-supervised administration of degludec or glargine for 4 months. School nurses observed daily blood ß-hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely. RESULTS: Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analysed. School-supervised injections of both basal insulins for 1-4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high p-value (17.2% vs. 9.0%, p = 0.3). HbA1c was unchanged in both groups. DISCUSSION: In youth with T1D at high risk for DKA, daily supervised long-acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school. CONCLUSION: Engaging school-based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes.

Use of Pharmacologic Prophylaxis Against Venous Thromboembolism in Hospitalized Injured Children.

Despite a practice management guideline and risk prediction model for venous thromboembolism (VTE), pediatric-specific evidence on pharmacologic prophylaxis is lacking. In a retrospective study, we characterized receipt of prophylaxis and explored its effectiveness in hospitalized injured patients below 18 years old using data from the Trauma Quality Improvement Program. Concordance of receipt of prophylaxis with guideline and predicted risk of VTE was estimated using κ statistic. Effectiveness was explored using cohorts matched based on the risk prediction model. A total of 11,165 (6.2%) of 180,932 patients received prophylaxis. Those who received prophylaxis were more commonly post-pubertal and more severely injured. Receipt of prophylaxis was fairly concordant with the guideline (κ=0.32) and predicted risk of VTE (κ=0.29). Receipt of prophylaxis was associated with higher rates of VTE likely due to confounding by indication. Low molecular weight heparin seemed more effective against VTE than unfractionated heparin (incidence rate ratio: 0.52; 95% confidence interval: 0.36, 0.75), but less effective when received ≥72 hours after admission to the hospital. We showed that hospitalized injured children did not commonly receive prophylaxis. We also showed that prophylaxis may be effective in hospitalized injured children, but it needs to be proven definitively in a randomized clinical trial.

North American Biliary Stricture Management Strategies in Children After Liver Transplantation: A Multicenter Analysis From the Society of Pediatric Liver Transplantation (SPLIT) Registry.

Biliary strictures affect 4%-12% of pediatric liver transplantations. Biliary strictures can contribute to graft loss if left untreated; however, there remains no consensus on the best course of treatment. Study objectives included analyses of outcomes associated with biliary stricture management strategies via percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP), or surgery. We identified pediatric liver transplantation recipients (2011-2016) with biliary strictures from the Society of Pediatric Liver Transplantation (SPLIT) registry and retrieved imaging, procedural, and operative reports from individual centers. Subanalyses were performed to specifically evaluate PTC and ERCP for "optimal biliary outcome" (OBO), defined as graft survival with stricture resolution and without recurrence or surgery. A total of 113 children with a median follow-up of 3.9 years had strictures diagnosed 100 days (interquartile range, 30-290) after liver transplantation; 81% were isolated anastomotic strictures. Stricture resolution was achieved in 92% within 101 days, more frequently with isolated anastomotic strictures (96%). 20% of strictures recurred, more commonly in association with hepatic artery thrombosis (32%). Patient and graft survival at 1 and 3 years were 99% and 98% and 94% and 92%, respectively. In a subgroup analysis of 79 patients with extrahepatic strictures managed by PTC/ERCP, 59% achieved OBO following a median of 4 PTC, and 75% following a median of 3 ERCP (P < 0.001). Among patients with OBO, those with ERCP had longer time intervals between successive procedures (41, 47, 54, 62, 71 days) than for PTC (27, 31, 36, 41, 48 days; P < 0.001). Allograft salvage was successful across all interventions. Stricture resolution was achieved in 92%, with 20% risk of recurrence. Resolution without recurrence was highest in patients with isolated anastomotic strictures and without hepatic artery thrombosis.

Clinical decision rule for obtaining peripheral blood cultures in febrile oncology patients.

BACKGROUND: The utility of peripheral blood cultures in pediatric oncology patients presenting with fever is controversial. A recent systematic review showed that about one in 40 bloodstream infections (BSIs) would be missed if only central venous line (CVL) cultures are obtained. OBJECTIVE: To derive a clinical decision rule for obtaining peripheral blood cultures in pediatric oncology patients presenting to a pediatric emergency department (PED) with fever and a CVL. DESIGN/METHOD: A retrospective chart review was performed on pediatric oncology patients referred to the PED for fever while on therapy. Logistic regression with a random intercept was used to determine independent predictors of BSI and generate a prediction model for obtaining peripheral blood cultures. The decision rule was generated from the best performance as measured by a receiver operator curve. Bootstrapping analysis was performed for internal validation. RESULTS: Predictors that were significant and independently associated with positive peripheral blood cultures included vasopressor support (odds ratio [OR] 16.5, 95% confidence interval [CI]: 2.80-97.71), acute myeloid leukemia (AML) diagnosis (OR 6.9, 95% CI: 1.81-25.98), hypotension (OR 4.0, 95% CI: 1.05-15.17), mucositis (OR 8.2, 95% CI: 2.48-27.01), and maximum temperature in PED ≥39°C (OR 6.6, 95% CI: 2.36-18.20). The area under the curve (AUC) for this model was 0.90 (95% CI: 0.82-0.97) in the derivation cohort and 0.90 (95% CI: 0.81-0.98) after the internal validation. CONCLUSIONS: We derived a clinical prediction model for deciding when to obtain peripheral blood cultures in febrile oncology patients with CVLs on active therapy. Future studies should focus on prospective and external validation of this diagnostic prediction tool.

CIDEA expression in SAT from adolescent girls with obesity and unfavorable patterns of abdominal fat distribution.

OBJECTIVE: This study investigated whether variations in cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) mRNA expression and protein levels are modulated by the pattern of abdominal fat distribution in adolescent girls with obesity. METHODS: This study recruited 35 adolescent girls with obesity and characterized their abdominal fat distribution by magnetic resonance imaging. Participants had only a periumbilical/abdominal (n = 14) or a paired abdominal and gluteal subcutaneous adipose tissue (SAT) biopsy (n = 21). CIDEA expression was determined by reverse transcription-polymerase chain reaction, CIDEA protein level by Western blot, and the turnover of adipose lipids and adipocytes by 2 H2 O labeling. In six girls, a second abdominal SAT biopsy was performed (after ~34.2 months) to explore the weight gain effect on CIDEA expression in abdominal SAT. RESULTS: CIDEA expression decreased in abdominal SAT from participants with high visceral adipose tissue (VAT)/(VAT+SAT); CIDEA inversely correlated with number of small adipocytes, with the increase in preadipocyte proliferation, and with adipogenesis. A strong inverse correlation was found between CIDEA protein level with the newly synthetized glycerol (r = -0.839, p = 0.0047). Following weight gain, an increase in adipocytes' cell diameter with a decrease in CIDEA expression and RNA-sequencing transcriptomic profile typical of adipocyte dysfunction was observed. CONCLUSIONS: Reduced expression of CIDEA in girls with high VAT/(VAT+SAT) is associated with adipocyte hypertrophy and insulin resistance.

A Prospective Study of the Effects of Sex Hormones on Lung Function and Inflammation in Women with Cystic Fibrosis.

Rationale: Epidemiologic studies demonstrate worse outcomes in women with cystic fibrosis (CF) than men. Women are colonized earlier with respiratory pathogens and have increased rates of pulmonary exacerbations after puberty and near ovulation. The etiology of this disparity is unclear, but sex hormones may contribute to these differences.Objectives: We sought to explore whether natural hormonal fluctuations and hormonal contraception associate with changes in lung function, respiratory symptoms, or inflammatory markers.Methods: We prospectively followed women with CF who were not on hormonal contraceptives and reported regular menstrual cycles. We captured study visits at points that corresponded with menses, ovulation, and the luteal phase. A subset of subjects were subsequently placed on a standard oral estrogen/progesterone combination contraceptive pill, ethinyl estradiol/norethindrone (loestrin), and reevaluated. Measurements included lung function, symptom questionnaires, sweat tests, blood for hormone concentrations, and sputum for inflammatory markers, bacterial density, and cytology.Results: Twenty-three women participated in this study. Hormone concentrations were as expected on and off hormonal contraception. At times of peak estrogen (ovulation), there was a significant increase in sputum proinflammatory cytokines (neutrophil-free elastase) and a corresponding pattern of decrease in lung function. Proinflammatory cytokines (IL-8, TNF-α, and neutrophil-free elastase) improved when placed on hormone contraception.Conclusions: Our results show that there are potentially important fluctuations in inflammatory biomarkers in the lungs that correlate with changes in lung function in women with CF. Larger studies evaluating the impact of sex hormones on airway inflammation and immune response are necessary to better understand the clinical impact of these responses.

Risks of venous thrombosis and bleeding in critically ill adolescents after trauma or major surgery.

BACKGROUND: The risks of venous thromboembolism (VTE) and bleeding in critically ill adolescents based on interventions received and anatomic site of trauma or major surgery may identify a cohort eligible for enrollment in a trial of pharmacologic prophylaxis. METHODS: This retrospective cohort study using the Virtual Pediatric Systems database included adolescents admitted to pediatric intensive care units after trauma or major surgery between 2013 and 2017. Mixed effects logistic regression was used to determine the adjusted risks of VTE and bleeding with central venous catheterization (CVC), mechanical ventilation (MV) and anatomic site of trauma or major surgery. The adjusted risks were used to identify the cohort eligible for enrollment. MEASUREMENTS AND MAIN RESULTS: VTE developed in 212 (0.8%) of 27,647 adolescents. The adjusted risk of VTE was >2% with CVC and 2 or more of MV and trauma or major surgery to the brain or abdomen. Excluding those with bleeds present on admission or at high risk of bleeding, 375 (1.4%) adolescents would be eligible for enrollment. CONCLUSIONS: VTE is generally uncommon in adolescents after trauma or major surgery. The small proportion of adolescents who are at high risk of VTE and at low risk of bleeding impacts the feasibility of a trial. LEVEL OF EVIDENCE: Prognostic Study Level II.

Patterns of medication use at end of life by pediatric inpatients with cancer.

OBJECTIVE: To describe medication utilization patterns by pediatric inpatients with cancer during their last week of life. METHODS: This retrospective study used data from the Vizient Clinical Database/Resource Manager, a national compilation of clinical and resource use data from over 100 academic medical centers and affiliates. Patients (0-21 years) with malignancy who died during hospitalization (2010-2017) were included (N = 1659). Medications were categorized as opioid, benzodiazepine, gastrointestinal related, chemotherapy, anti-infectives, or vasopressors. Exposure to each group was ascertained for all patients at 1 week and 1 day prior to death. Factors associated with exposure were examined using generalized estimating equations, and summarized using adjusted odds ratios (aORs). RESULTS: Over the last week of life, there was increased use of opioids (76% to 82%, aOR = 1.55, P < .001) and benzodiazepines (53% to 66%, aOR = 1.36, P = .02), while gastrointestinal-related medication use decreased (92% to 89%, aOR = 0.69, P = .001). Patients had decreased exposure to chemotherapy (10% to 5%, aOR = 0.46, P < .001) and anti-infectives (82% to 73%, aOR = 0.41, P = .002). Vasopressor use increased as death approached (15% to 28%, aOR = 1.67, P = .04). Factors significantly associated with exposure varied with medication category, and included age, race, length of stay, malignancy type, death in the intensive care unit, history of hematopoietic stem cell transplant, and do-not-resuscitate status. CONCLUSION: During the week preceding death, administration of symptom management medications increased for children with cancer, but use was not universal. Potentially life-sustaining medications were often continued. Variability in utilization suggests differences in provider/family decision making that warrant further study to develop an evidence-based approach to end-of-life care.

The association between anti-Müllerian hormone and vitamin 25(OH)D serum levels and polycystic ovarian syndrome in adolescent females.

BACKGROUND: High anti-Müllerian hormone (AMH) levels and 25-hydroxyvitamin D [25(OH)D] deficiency have been associated with polycystic ovarian syndrome (PCOS) in adult women, and implicated in its pathogenesis. Herein we determined if the level of both AMH and 25(OH)D are altered in adolescent females with clinical features of PCOS. METHODS: This is a cross-sectional study utilizing a retrospective chart review of 128 patients aged 12-20 referred to an academic adolescent gynecology and endocrinology clinic for an evaluation of suspected PCOS. Unadjusted comparisons of AMH and 25(OH)D distributions between subjects with and without PCOS were performed using the Wilcoxon Rank Sum test. Quantile regression was used to compare the median AMH and 25(OH)D between subject groups; adjusting for race, ethnicity, BMI, insurance type, age, and season when bloodwork was performed. RESULTS: Seventy-four subjects were classified as having PCOS by meeting ≥2 of the three Rotterdam diagnostic criteria, and 47 subjects met only one Rotterdam diagnostic criteria, and were used as the comparative non-PCOS group. There were statistically significant unadjusted differences in median levels of AMH and 25(OH)D. In the adjusted analyses, median AMH was significantly higher in the PCOS group compared to the non-PCOS group (+ 2.39 ng/mL, 95% CI 0.43, 4.35, p = 0.018); 25(OH)D was significantly lower in the PCOS group (- 9.01 ng/mL, 95% CI -14.49, - 3.53 p = 0.001). In our sample, adolescents in both groups had insufficient 25(OH)D level (22 ng/mL) and elevated BMI (32.2 kg/m2). CONCLUSIONS: Adolescents with PCOS display high levels of AMH and low 25(OH)D levels. Since traditional clinical markers of PCOS may be physiologic in adolescents, AMH and 25(OH)D may be used as surrogate markers of PCOS risk in adolescents.

De novo damaging variants associated with congenital heart diseases contribute to the connectome.

Congenital heart disease (CHD) survivors are at risk for neurodevelopmental disability (NDD), and recent studies identify genes associated with both disorders, suggesting that NDD in CHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that NDD in CHD may be attributable to genes altering both neural connectivity and cardiac patterning. To assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. CHD cases had more protein truncating and deleterious missense DNVs among connectome genes compared to controls (OR = 5.08, 95%CI:2.81-9.20, Fisher's exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02-6.73, Fisher's exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11, CHD7, CHD4, KMT2A, NOTCH1, ADNP, SMAD2, KDM5B, NSD2, FOXP1, MED13L, DYRK1A; one-tailed binomial test P ≤ 4.08E-05) contributed to the connectome. These data suggest that NDD in CHD patients may be attributable to genes that alter both cardiac patterning and the connectome.

Perceptions of Neonatal Palliative Care: Similarities and Differences between Medical and Nursing Staff in a Level IV Neonatal Intensive Care Unit.

Background: A significant number of newborns are affected by life-limiting or life-threatening conditions. Despite this prevalence, there are inconsistencies in attitudes toward, and delivery of, neonatal palliative care. Implementing neonatal palliative care practice requires a multidisciplinary, collaborative effort. Objective: To examine institutional and individual barriers to and facilitators of neonatal palliative care from both medical and nursing perspectives. Design/Setting/Subjects: A prospective cross-sectional study design was used to collect data using the Neonatal Palliative Care Attitude Scale (NiPCAS) survey from medical providers and nurses in a 64-bed level IV neonatal intensive care unit in the United States. The response rate was 67%. Measurements: The NiPCAS survey included 26 attitudinal questions on a Likert scale. The instrument included three subscales: organization, resources, and clinician, in addition to other questions. Results: Six facilitators to neonatal palliative care were identified: (1) support of palliative care by the health care team, (2) support of palliative care by medical and nursing practice, (3) agreement that palliative care is as important as curative care, (4) parental involvement in decision making, (5) recognition of the importance of palliative care education, and (6) prioritizing pain relief. Three barriers to neonatal palliative care were highlighted: (1) a physical environment that is not conducive to providing palliative care, (2) technological obligations and parental demands, and (3) the societal belief that babies should not die. In addition, there were differences between medical and nursing staffs' attitudes on several topics. Conclusions: Several facilitators and barriers of neonatal palliative care were identified. There were similarities and differences in perceptions of neonatal palliative care between medical and nursing staff. Future work should be done to strengthen facilitators and to mitigate barriers.

Variable management strategies for NEC totalis: a national survey.

BACKGROUND/OBJECTIVES: Necrotizing enterocolitis (NEC) is a serious disease linked to prematurity. A variant, NEC totalis, is associated with nearly 100% mortality. There is wide variation in counseling practices for NEC totalis. Our objectives are to determine what treatment options, if any, are offered to families, and which factors influence these decisions. METHODS: An anonymous survey was distributed to members of the AAP Sections on Neonatal-Perinatal Medicine and Pediatric Surgery. Data were analyzed utilizing chi-square tests and Spearman correlations, where applicable. RESULTS: In the setting of NEC totalis, 90% of the 378 respondents viewed offering life-sustaining interventions (LSI) as ethically permissible and 87% felt that transfer to another center willing to provide LSI should be considered; however, only 43% reported offering LSI to families. CONCLUSIONS: Management of NEC totalis remains challenging and significant practice variability persists. Most respondents do not offer ongoing medical/surgical management, despite believing it is an ethically permissible option.

Epidemiology of Clinically Relevant Bleeding in Critically Ill Adolescents.

OBJECTIVES: The epidemiology of clinically relevant bleeding in critically ill adolescents, particularly those who are at high risk of venous thromboembolism, is unclear. In preparation for a randomized clinical trial of pharmacologic prophylaxis against venous thromboembolism, we characterized the epidemiology of clinically relevant bleeding in critically ill adolescents. DESIGN: Post hoc analysis of data from a pediatric multicenter observational study of venous thromboembolism. SETTING: Six PICUs. PATIENTS: Adolescents 13-17 years old who received cardiac or pulmonary support for at least 48 hours were eligible. Those admitted with venous thromboembolism or receiving therapeutic anticoagulation were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Adolescents (n = 88) were followed daily for the development of any bleeding event. The severity of the event was categorized based on the definitions by the International Society on Thrombosis and Haemostasis. The frequency of clinically relevant bleeding was 29.5% (95% CI, 20.3-40.2%) or 3.7 events (95% CI, 2.5-5.4 events) per 100 patient-days. Adolescents with venous thromboembolism were more likely to develop clinically relevant bleeding (hazard ratio, 2.06; 95% CI, 1.08-3.94). Age was negatively associated with clinically relevant bleeding (hazard ratio for every 1-year increase in age: 0.68; 95% CI, 0.58-0.79). In contrast, predicted risk of mortality (hazard ratio for every 0.10 increase in risk: 1.35; 95% CI, 1.05-1.74) and admission for trauma or surgery (hazard ratio: 2.04; 95% CI, 1.21-3.44) were positively associated with clinically relevant bleeding. The association of clinically relevant bleeding with medications, interventions, or laboratory tests, including mechanical ventilation and pharmacologic prophylaxis with anticoagulation, did not reach statistical significance. Adolescents with clinically relevant bleeding stayed in the hospital longer than those without clinically relevant bleeding. CONCLUSIONS: Clinically relevant bleeding is common in critically ill adolescents who are at high risk of venous thromboembolism. Admission for trauma or surgery can be used to stratify the risk of clinically relevant bleeding in these adolescents.

Angiopoietin Level Trajectories in Toddlers With Severe Sepsis and Septic Shock and Their Effect on Capillary Endothelium.

OBJECTIVE: Angiopoietins are postulated diagnostic biomarkers in children and adults with severe sepsis and septic shock. The diagnostic value of angiopoietins in children less than 5 years old has not been established, nor has their effect on permeability in the capillary microvasculature. We aim to determine if levels of angiopoietin-1 or -2 (angpt-1, -2) are diagnostic for severe sepsis/shock in young children and whether they affect the permeability of cultured human dermal microvascular endothelial cells (HDMEC). DESIGN: Prospective observational study of children < 5 years old. Patients were classified as non-systemic inflammatory response syndrome (SIRS), SIRS/sepsis and severe sepsis/septic shock. SETTING: Tertiary care pediatric hospitals. PATIENTS: Critically ill children. INTERVENTIONS: None. MEASUREMENTS: Plasma angpt-1 and -2 levels were measured with enzyme-linked immunoassays. Expression of angpt-2 in endothelial cells was assessed with quantitative polymerase chain reaction. Permeability changes in cultured HDMECs were assessed with transendothelial electrical resistance measurements. RESULTS: Angpt-1 levels were significantly higher in younger children compared with levels found in previous study of older children across disease severity (all P < 0.001). Angpt-2 was significantly higher in this cohort with severe sepsis/septic shock compared with children without SIRS and SIRS/sepsis (all P < 0.003). Angpt-2/1 ratio was also elevated in children with severe sepsis/septic shock but an order of magnitude less than older children (P < 0.02, P = 0.002). Angpt-1 and -2 did not affect basal HDMEC permeability or modulate leak in isolation or in the presence of tumor necrosis factor (TNF). CONCLUSIONS: Angpt-2 levels and the angpt-2/1 ratio are appropriate diagnostic biomarkers of severe sepsis/septic shock in children less than 5 years old. Neither angpt-1 nor -2 affects basal HDMEC permeability alone or modulates TNF induced capillary leak.

Reducing Radiation Exposure in Cardiac Catheterizations for Congenital Heart Disease.

Ionizing radiation exposure is a necessary risk entailed during congenital cardiac catheterizations. The congenital catheterization lab at Yale New Haven Children's Hospital employed quality improvement strategies to minimize radiation exposure in this vulnerable population. In two phases, we implemented six interventions, which included adding and utilizing lower fluoroscopy and digital angiography (DA) doses, increasing staff and physician radiation awareness, focusing on tighter collimation, and changing the default fluoroscopy and DA doses to lower settings. Post-intervention data were collected prospectively for all procedures in the congenital catheterization lab and compared to pre-intervention radiation data collected retrospectively. Radiation exposure was measured in total air kerma (mGy), dose area product per body weight (DAP/kg) (µGy m2/kg), and fluoroscopy time (min). Data were collected for a total of 312 cases. In considering all procedures, the DAP/kg decreased by 67.6% and air kerma decreased by 63%. Fluoroscopy time did not change over the study period. Significant decreases in radiation exposure (DAP/kg) by procedure type were seen for atrial septal defect, patent ductus arteriosus, and transcatheter pulmonary valve procedures with a 45%, 42% and 83% decrease, respectively. Air kerma decreased significantly for ASD and PDA procedures with an 80% and 72% decrease, respectively. When compared to national benchmarks, the median DAP/kg and air kerma for these procedures are lower at our institution. The decreases continue to be sustained 2 years post-interventions. Systems-based interventions can be readily implemented in the congenital cardiac catheterization lab with dramatic and sustainable radiation dose reduction for patients.

Risk factors for tracheostomy requirement in extremely low birth weight infants.

AIM: To identify variables that affect the risk of tracheostomy in a population of extremely low birth weight (ELBW) infants. METHODS: A retrospective matched case-control study was conducted. ELBW infants with a tracheostomy were compared with controls without tracheostomy. Data collection included demographics, detailed information about each intubation and extubation attempt, the use of steroids and the presence of comorbidities. Statistical analyses include conditional logistic regression and Poisson regression for clustered observations. RESULTS: Twenty-eight ELBW infants with a tracheostomy were identified. Mean gestational age for both cases and controls was 25 weeks (22-29) and 67.9% were males. Tracheostomy was performed on average on day of life 118 (95%CI: 107-128) and weight at tracheostomy was 2877 g (95%CI: 2657-3098). In the final model, cumulative days with an endotracheal tube (ETT) and total number of intubation episodes were associated with a tracheostomy. For each additional day of intubation, odds of tracheostomy increased by 11% (OR = 1.11, 95%CI: 1.01, 1.23) and with each new intubation episode/failed extubation episode, odds of tracheostomy increased by 150% from the previous episode (OR = 2.5, 95%CI: 1.2, 5.2). CONCLUSIONS: Greater cumulative exposure to ETT ventilation and number of intubations is associated with having a tracheostomy.

Prediction of Catheter-Associated Thrombosis in Critically Ill Children.

OBJECTIVE: We determined whether in critically ill children with an untunneled central venous catheter, the risk of catheter-associated deep venous thrombosis can be predicted within 24 hours after insertion of the catheter. DESIGN: Secondary analysis of two multicenter prospective cohort studies. SETTING: PICUs in Northeastern United States. PATIENTS: A total of 175 children admitted to the PICU within 24 hours after insertion of an untunneled central venous catheter who did not receive anticoagulation were included. Of these, 53 (30.3%) developed catheter-associated thrombosis detected with active surveillance with ultrasonography. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used logistic regression (models 1 and 2) and recursive partitioning (models 3 and 4) methods to develop risk prediction models with predictors present at any time while catheterized (models 1 and 3), or within 24 hours after insertion of the catheter (models 2 and 4). Age, recent surgery, catheter in the subclavian vein, and blood product transfusion were included in models 1 and 2. Areas under the receiver operating characteristic curves were similar for these models (model 1: 0.80 vs model 2: 0.80; p = 0.44). Except for recent surgery, predictors in model 1 were identified as partitioning variables for model 3. In addition to the predictors in model 2, severity of illness was used in partitioning for model 4. The area under the curve of model 3 appeared smaller than that of model 4 (0.75 vs 0.80; p = 0.08). Groups of children at low, intermediate, and high risks of catheter-associated thrombosis were identified using model 4. CONCLUSIONS: Critically ill children at high risk of catheter-associated thrombosis can be identified within 24 hours after insertion of an untunneled central venous catheter.

Methylation of twelve CpGs in human papillomavirus type 16 (HPV16) as an informative biomarker for the triage of women positive for HPV16 infection.

An accurate biomarker for the follow-up of women positive for human papillomavirus type 16 (HPV16) DNA may improve the efficiency of cervical cancer prevention. Previously, we analyzed all 113 HPV16 CpGs in cervical cytology samples and discovered differential methylation at different stages of premalignancy. In the current study, we identified a methylation biomarker consisting of a panel of 12 HPV16 CpG sites in the E5, L2, and L1 open reading frames, and tested whether it fulfilled three necessary conditions of a prospective biomarker. A total of 33 cytology samples from North American and West African women with all grades of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) were analyzed by using DNA bisulfite sequencing. The results showed (i) a highly significant trend for increasing HPV16 biomarker methylation with increasing histologic severity (P < 0.0001), (ii) 100% sensitivity for ICC over a wide range of methylation cutoff scores; 80% detection of CIN3 at cutoff scores up to 39% methylation, and (iii) substantially lower detection of CIN2, from 0% to 71%, depending on the cutoff score. Our results support the prognostic potential of the HPV16 methylation biomarker for the triage to colposcopy of women with HPV16-positive screening tests and, eventually, for the management of women with HPV16-positive CIN2.