Advancing future research on sepsis outcomes in adolescents with SUD: integrating AI, accounting for temporal trends, and enhancing exposure classification.
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Letter↗
Biomedical subjects
Neal J Thomas
Publications and source records attributed to Neal J Thomas.
Surfactant protein A2 (SP-A2) variants expressed in CHO cells stimulate phagocytosis of Pseudomonas aeruginosa more than do SP-A1 variants.
Surfactant protein A (SP-A) enhances phagocytosis of Pseudomonas aeruginosa. Two functional genes, SP-A1 and SP-A2, encode human SP-A. As we showed before, baculovirus-mediated insect cell-expressed SP-A2 enhances the association of P. aeruginosa with rat alveolar macrophages (rAMs) more than does SP-A1. However, true phagocytosis (internalization) was not shown, and insect cell derived proteins lack or are defective in certain mammalian posttranslational modifications that may be important for SP-A1 and SP-A2 activity and specificity. Here we used SP-A1 (6A(2), 6A(4)) and SP-A2 (1A(0), 1A(1)) allele variants expressed by CHO (Chinese hamster ovary) mammalian cells to study their effect on association and/or internalization of P. aeruginosa by rAMs and/or human AMs (hAMs) and to study if phagocytosis can be modulated differentially and/or more effectively by CHO cell-expressed SP-A variants than by insect-cell expressed SP-A variants. For cell association and internalization assessments, light microscopy and fluorescence-activated cell sorter analyses were used, respectively. We found the following for the first time. (i) SP-A2 variants enhanced phagocytosis (cell association and/or internalization) of P. aeruginosa more than SP-A1 variants did, and the cell association correlated with internalization. (ii) Differences in the activities of SP-A variants were observed in the following order: 1A(1)>1A(0)>6A(2)>6A(4). (iii) rAMs, although more active than hAMs, are an appropriate model, as SP-A2 variants exhibited activity higher than that seen for SP-A1 variants with either rAMs or hAMs. (iv) CHO cell-expressed SP-A was considerably more active than insect cell-expressed variants. We conclude that SP-A2 variants stimulate phagocytosis of P. aeruginosa more effectively than SP-A1 variants and that posttranslational modifications positively influence the phagocytic activity of SP-A.
Animals↗
Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health.
The human surfactant protein A (SP-A) locus consists of two functional genes (SP-A1, SP-A2) with gene-specific products exhibiting qualitative and quantitative differences. The aim here was twofold: 1) generate SP-A1 gene-specific antibody, and 2) use this to assess gene-specific SP-A content in the bronchoalveolar lavage fluid (BALF). An SP-A1-specific polyclonal antibody (hSP-A1_Ab(68-88)_Col) was raised in chicken, and its specificity was determined by immunoblot and ELISA using mammalian Chinese hamster ovary (CHO) cell-expressed SP-A1 and SP-A2 variants and by immunofluorescence with stably transfected CHO cell lines expressing SP-A1 or SP-A2 variants. SP-A1 content was evaluated according to age and lung status. A gradual decrease (P < 0.05) in SP-A1/SP-A ratio was observed in healthy subjects (HS) with increased age, although no significant change was observed in total SP-A content among age groups. Total SP-A and SP-A1 content differed significantly between alveolar proteinosis (AP) patients and HS, with no significant difference observed in SP-A1/SP-A ratio between AP and HS. The cystic fibrosis (CF) ratio was significantly higher compared with AP, HS, and noncystic fibrosis (NCF), even though SP-A1 and total SP-A were decreased in CF compared with most of the other groups. The ratio was higher in culture-positive vs. culture-negative samples from CF and NCF (P = 0.031). A trend of an increased ratio was observed in culture-positive CF (0.590 +/- 0.10) compared with culture-positive NCF (0.368 +/- 0.085). In summary, we developed and characterized an SP-A1 gene-specific antibody and used it to identify gene-specific SP-A content in BALFs as a function of age and lung health.
Aging↗
High-throughput DNA methylation profiling using universal bead arrays.
We have developed a high-throughput method for analyzing the methylation status of hundreds of preselected genes simultaneously and have applied it to the discovery of methylation signatures that distinguish normal from cancer tissue samples. Through an adaptation of the GoldenGate genotyping assay implemented on a BeadArray platform, the methylation state of 1536 specific CpG sites in 371 genes (one to nine CpG sites per gene) was measured in a single reaction by multiplexed genotyping of 200 ng of bisulfite-treated genomic DNA. The assay was used to obtain a quantitative measure of the methylation level at each CpG site. After validating the assay in cell lines and normal tissues, we analyzed a panel of lung cancer biopsy samples (N = 22) and identified a panel of methylation markers that distinguished lung adenocarcinomas from normal lung tissues with high specificity. These markers were validated in a second sample set (N = 24). These results demonstrate the effectiveness of the method for reliably profiling many CpG sites in parallel for the discovery of informative methylation markers. The technology should prove useful for DNA methylation analyses in large populations, with potential application to the classification and diagnosis of a broad range of cancers and other diseases.
Base Sequence↗
The impact of pediatric trauma in the Amish community.
OBJECTIVE: To describe the epidemiology of trauma in Amish children and to determine differences in treatment and outcome related to injury mechanism. STUDY DESIGN: In this retrospective review, data were collected on all Amish children with trauma requiring hospital admission. Demographic, interventional, and outcome data were collected. Categorical outcomes were compared by using chi-square, logistic regression, or Fisher exact test; continuous outcomes were compared with analysis of variance. RESULTS: A total of 135 trauma admissions were studied. There was a significant difference of proportion of injury by month (P < .01). The most common mechanisms of injury were falls (39%), buggy versus motor vehicle accidents (MVA; 16%), and animal injuries (14%). A total of 41% of patients required operative procedures, and 50% of subjects required intensive care. Animal injuries and buggy versus MVA were significantly associated with a requirement for surgery, increased length of stay, and increased severity (all P < .01). The overall mortality rate was 3%. There were significant associations between mechanism of injury and outcome scores (P < .05) and hospital charges (P < .05). CONCLUSIONS: The spectrum of traumatic injuries is unique among Amish children. These injuries contribute significantly to morbidity and mortality and impose a large monetary burden on the Amish community. Education may decrease the incidence of these events.
Accidental Falls↗
Safety and efficacy of sedation with propofol for transoesophageal echocardiography in children in an outpatient setting.
BACKGROUND: Transoesophageal echocardiography has become a powerful tool in the diagnosis and management of children with congenital cardiac malformations. Unlike adults, children will not tolerate transoesophageal echocardiography under light sedation. This study was undertaken, therefore, to evaluate the safety and efficacy of deep sedation with propofol for transoesophageal echocardiography in children examined in an outpatient setting. METHODS: This is a retrospective study of patients undergoing transoesophageal echocardiography with propofol given in bolus aliquots to achieve a level of sedation adequate to insert the transoesophageal echocardiographic probe and maintain sedation throughout the procedure. RESULTS: We included a total of 118 patients, 57% being male, with a mean age of 12.9 years. Adequate sedation was achieved using a mean propofol dose of 8.3 milligrams per kilogram, with the dose per kilogram decreasing concomitant with increasing weight of the patient. Patients less than two years of age were intubated for the procedure. There were no clinically significant changes in cardiac function or haemodynamics. Non-intubated patients received supplemental oxygen prior to, or just after, the onset of sedation, with transient hypoxaemia observed in one-fifth. Complications were rare, with minor problems occurring in 7.6%, and major ones in 4%. CONCLUSIONS: Transoesophageal echocardiography can be performed on an outpatient basis in children with a wide spectrum of congenital cardiac malformations, and propofol is an ideal sedative agent in this setting. Although not common, preparations must be made for significant haemodynamic and respiratory complications. In our study, we intubated all the children under 2 years of age.
Adolescent↗
Opioids causing a back up in the pediatric intensive care unit? No solution yet.
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Adolescent↗
Family-based association tests suggest linkage between surfactant protein B (SP-B) (and flanking region) and respiratory distress syndrome (RDS): SP-B haplotypes and alleles from SP-B-linked loci are risk factors for RDS.
Genetic variants of surfactant protein B (SP-B) have been associated with respiratory distress syndrome (RDS) in the prematurely born infant. We wished to determine linkage between RDS and SP-B single nucleotide polymorphisms (SNPs) [-18 (A/C), 1013 (A/C), 1580 (C/T), and 9306 (A/G)] or SP-B-linked microsatellite [(D2S388, D2S2232, (AAGG)n, and GATA41E01 (or D2S1331)] loci and identify susceptibility or protective alleles and haplotypes. We genotyped 132 families consisting of one or two parents and at least one child affected with RDS and performed biallelic and multiallelic family-based association test (FBAT) analysis, and extended transmission disequilibrium test (ETDT). ETDT analysis identified the microsatellite SP-B-linked loci (except D2S2232) to be linked to RDS. One allele from each of these three marker loci contributes to the risk of RDS. Multiallelic FBAT analysis detected a signal of linkage for the region of the four SNP loci. Three haplotypes within this region contribute to RDS risk. Although no other region showed significant linkage as judged by multiallelic FBAT, biallelic FBAT analysis revealed three potential susceptibility haplotypes formed by two to four loci within the SP-B and SP-B-linked microsatellite region. Each haplotype included GATA41E01, which was identified by ETDT analysis to be linked to RDS. We conclude that SP-B or SP-B-linked loci are linked to RDS and certain alleles or haplotypes are susceptibility or protective factors for the development of RDS in infants born prematurely.
Adult↗
Deletions within a CA-repeat-rich region of intron 4 of the human SP-B gene affect mRNA splicing.
Length variants within a CA-repeat-rich region of intron 4 of the human SP-B (pulmonary surfactant protein-B) gene are associated with several lung diseases. The hypothesis that SP-B intron 4 affects mRNA splicing was studied. SP-B minigenes containing exons 1-6 with a normal-sized intron 4 (pBi4normal) or intron 4 containing deletions (pBi4del) of 193, 211, 264 or 340 bp were expressed in CHO (Chinese hamster ovary) cells by transient transfection. Two forms of SP-B transcripts, normal and incompletely spliced, were detected. With pBi4normal, normal-sized SP-B mRNA was the predominant form and a very low amount of incompletely spliced mRNA was present, whereas with the pBi4del variants the amount of normal SP-B mRNAs was lower and the amount of incompletely spliced mRNA was relatively high. Reverse transcription-PCR results and sequencing data indicated that the incompletely spliced SP-B RNA contained intron 4 sequence, and this incompletely spliced RNA was also observed in normal lung. Lung cancer tissues with intron 4 deletions exhibited a larger amount of abnormally spliced RNAs compared with normal lung tissue or cancerous tissue with normal-sized intron 4. The results indicate that intron 4 length variants affect SP-B mRNA splicing, and that this may contribute to lung disease.
Animals↗
Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial.
CONTEXT: Despite evidence that patients with acute lung injury (ALI) have pulmonary surfactant dysfunction, trials of several surfactant preparations to treat adults with ALI have not been successful. Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant (calfactant) containing high levels of surfactant-specific protein B may be beneficial. OBJECTIVE: To determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, blinded trial of calfactant compared with placebo in 153 infants, children, and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003. Twenty-one tertiary care pediatric intensive care units participated. Entry criteria included age 1 week to 21 years, enrollment within 48 hours of endotracheal intubation, radiological evidence of bilateral lung disease, and an oxygenation index higher than 7. Premature infants and children with preexisting lung, cardiac, or central nervous system disease were excluded. INTERVENTION: Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart. MAIN OUTCOME MEASURES: Ventilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation. RESULTS: The calfactant group experienced an acute mean (SD) decrease in oxygenation index from 20 (12.9) to 13.9 (9.6) after 12 hours compared with the placebo group's decrease from 20.5 (14.7) to 15.1 (9.0) (P = .01). Mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although ventilator-free days were not different. More patients in the placebo group did not respond to conventional mechanical ventilation. There were no differences in long-term complications. CONCLUSIONS: Calfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed.
Adolescent↗
Epoprostenol and home mechanical ventilation for pulmonary hypertension associated with chronic lung disease.
Pulmonary hypertension (PH) can be associated with bronchopulmonary dysplasia (BPD) of infancy, and mortality in these pediatric patients is high without aggressive medical treatment. Continuous intravenous epoprostenol (prostacyclin) was shown to lower pulmonary artery pressures (PAP) in children with idiopathic pulmonary arterial hypertension (PAH), formerly referred to as primary pulmonary hypertension. We report on the first case of long-term home ventilation in combination with chronic intravenous epoprostenol in a child with severe pulmonary hypertension associated with chronic lung disease. This aggressive combination resulted in significant improvement in pulmonary artery pressures, substantial improvement in quality of life, and eventual discontinuation of home ventilation.
Antihypertensive Agents↗
Efficacy of bystander cardiopulmonary resuscitation and out-of-hospital automated external defibrillation as life-saving therapy in commotio cordis.
We report a child who sustained commotio cordis after being struck by a baseball, and offer documentation of the advantages of having readily available access to bystander cardiopulmonary resuscitation (CPR) and an automated external defibrillator (AED). We suggest that communities and school districts reexamine the need for accessible AEDs and CPR-trained coaches at organized sporting events for children.
Adolescent↗
Altered chemokine response in an animal model of multiple organ dysfunction syndrome induced by zymosan.
PURPOSE: The aim of this study was to determine the monocyte chemoattractant protein-1 (MCP-1) response over time in an animal model of multiple organ dysfunction syndrome (MODS). METHODS: On day 0, rats were randomized to receive an intraperitoneal injection of zymosan at a dose of 1 mg/g of body weight (n = 36) or vehicle (n = 9). Serum, peritoneal lavage (PL) fluid, and bronchoalveolar lavage (BAL) fluid were collected from 3 rats in the control group and 6 to 7 rats in the zymosan group at days 1, 5, and 12. Monocyte chemoattractant protein-1 concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: The authors observed a 47% mortality in the zymosan-treated rats. Monocyte chemoattractant protein-1 levels were unchanged in the serum, PL, and BAL of control animals. Both serum and PL MCP-1 were significantly higher in zymosan-treated rats on days 1 (P < .01) and 5 (P < .05) when compared with controls. By day 12, no difference between the 2 groups was observed. No significant difference was noted in BAL MCP-1. CONCLUSIONS: Chemokines are increased systemically and locally during MODS. The fact that MCP-1 is significantly higher early in the course of MODS may suggest that this chemokine is important in the early inflammatory changes that lead to MODS later in the course of this illness.
Animals↗
Cost-effectiveness of exogenous surfactant therapy in pediatric patients with acute hypoxemic respiratory failure.
OBJECTIVE: To determine whether the use of exogenous surfactant (Infasurf) in pediatric acute hypoxemic respiratory failure is cost-effective. DESIGN: Deterministic cost-effectiveness analysis based on a Markov model. The model was calibrated using outcomes and resource utilization observed in a multiple-centered, prospective, randomized, controlled unblinded trial of Infasurf in pediatric acute hypoxemic respiratory failure. Costs were short-run direct costs estimated from the perspective of the hospital as provider. Primary outcomes were expected costs, expected survival rates, and incremental cost per life saved. SETTING: Patients in the trial were treated in one of eight pediatric intensive care units of tertiary medical centers. PATIENTS: Forty-two children with acute hypoxemic respiratory failure who were randomized to receive either standard therapy or exogenous surfactant in addition to standard therapy. MEASUREMENTS AND MAIN RESULTS: Our baseline analysis suggests that for a 10-kg child, the Infasurf strategy is both less costly (62,922 US dollars vs. 74,006 US dollars) and more effective (survival: 90.3% vs. 85.1%) and therefore dominates standard treatment. Cost savings were realized in the model because patients in the surfactant group were more likely to leave the pediatric intensive care unit sooner. The Infasurf strategy continues to dominate for children up to 60 kg. At 70 kg, the cost to save an additional life using the Infasurf strategy is 79,805 US dollars, which is still cost-effective if the provider is willing to make this tradeoff. CONCLUSIONS: For the majority of pediatric patients with acute hypoxemic respiratory failure, exogenous surfactant is cost-effective. If the use of this medication becomes standard care, a greater variety of packaging sizes could lead to decreased acquisition costs and increase the number of patients for whom this treatment is cost-effective.
Acute Disease↗
Prospective assessment of guidelines for determining appropriate depth of endotracheal tube placement in children.
OBJECTIVE: To determine whether multiplying the internal diameter of the endotracheal tube (ETT) by 3 (3x ETT size) is a reliable method for determining correct depth of oral ETT placement in the pediatric population. DESIGN: Prospective, observational. SETTING: University-affiliated, 12-bed pediatric intensive care unit. PATIENTS: Orally intubated pediatric intensive care unit patients of < or =12 yrs of age. INTERVENTIONS: Demographics, ETT size, and depth of ETT placement measured from the lip were obtained. Correct placement, defined as the tip of the ETT below the thoracic inlet and > or =0.5 cm above the carina, was determined by chest radiograph. MEASUREMENTS AND MAIN RESULTS: Suggested ETT size based on the Pediatric Advanced Life Support (PALS) age-based formula and the Broselow tape-length-based guidelines were determined. A total of 174 of 226 ETTs (77%) were correctly positioned. If practitioners utilized the 3x ETT size for the actual tubes chosen, 170 of 226 (75%) would have been accurately placed. More accurate were the 3x PALS-based ETT size (81%) and 3x Broselow-suggested ETT size (85%). The use of the Broselow ETTs to determine the depth would have led to a significantly improved ETT position (p = .009) compared with the actual ETT. CONCLUSION: The commonly used formula of 3x tube size for ETT depth in children results in 15-25% malpositioned tubes. Practitioners can improve the reliability of this formula by utilizing the recommended ETT size as suggested by the Broselow tape. A more reliable method is necessary to avoid ETT malposition.
Age Factors↗
Idiopathic thrombocytopenic purpura complicated by an intracranial hemorrhage secondary to an arteriovenous malformation.
OBJECTIVE: To report a case of idiopathic thrombocytopenic purpura (ITP) complicated by an intracranial hemorrhage (ICH) in a child with a previously undiagnosed arteriovenous malformation. CASE: We describe a child with known ITP who developed a severe headache, was evaluated in an emergency department of a community hospital, and was found by computer tomography (CT) scan to have an ICH. Despite treatment with platelets, corticosteroids, and intravenous immunoglobulin, she subsequently developed an acute change in mental status. A second CT scan showed that the hemorrhage had significantly increased in size despite treatment. The patient underwent an emergent splenectomy prior to a craniotomy to remove the hemorrhage. At the time of surgery, it was discovered that she had an arteriovenous malformation at the sight of the hemorrhage. Her recovery was unremarkable and she was discharged to home with no neurologic sequelae. CONCLUSIONS: ICH is a rare but life-threatening complication of ITP. Neurologic symptoms in a child with ITP should be quickly evaluated by CT scan. Most experts suggest careful observation for most cases of ITP. However, when neurologic symptoms occur, more aggressive treatment options must be used. Care of this child included an emergency splenectomy prior to her craniotomy. Pediatric emergency medicine practitioners must be aware of these neurologic symptoms and must not hesitate to involve pediatric surgeons and neurosurgeons in the care of the child. Prompt recognition and early intervention are the keys to improving outcomes when ICH complicates ITP.
Child↗
Continuous versus intermittent cerebrospinal fluid drainage after severe traumatic brain injury in children: effect on biochemical markers.
Drainage of cerebrospinal fluid (CSF) is routinely used in the treatment of severe traumatic brain injury (TBI), either continuously or intermittently in response to increases in intracranial pressure (ICP). There has been little study of the effect of CSF drainage method on the biochemistry, pathophysiology or outcome of TBI in adults or children. Having previously reported that a variety of markers of injury or repair increase in CSF after severe TBI, we chose to evaluate directly the effect of CSF drainage method on the biochemistry and volume of CSF drained as well as ICP. We hypothesized that concentrations of these markers would be similar in CSF drained continuously vs intermittently. We compared CSF levels of markers of neuronal injury (neuron specific enolase, [NSE]), glial injury (s100B), inflammation (interleukin-6 [IL-6]), and regeneration (vascular endothelial growth factor [VEGF]) (measured by ELISA) in 80 CSF samples from 19 severely injured children whose CSF was drained continuously (n = 13) versus intermittently (n = 6) as part of standard care in two institutions. Compared to continuous CSF drainage, intermittent drainage of CSF was associated with twofold greater CSF concentrations of NSE, s100B, IL-6 and VEGF (p < 0.05) and with about half the volume of CSF removal than continuous drainage (p = 0.002). The resulting elimination (concentration x volume) of these biochemicals, however, was not influenced by drainage method. Patients treated with continuous drainage had lower mean ICPs than those with intermittent drainage (13.6 +/- 0.69 vs. 21.8 +/- 0.95 mm Hg, p < 0.0001). We conclude that the method of CSF drainage greatly affects concentrations of CSF markers after TBI and may influence ICP. The influence of method on CSF marker concentration must be kept in mind when interpreting studies of CSF biomarkers. The striking difference in biomarker concentration, CSF volume drained, and ICP suggests the need for a randomized trial directly comparing these two approaches in infants and children with severe TBI.
Adolescent↗
Decreasing unplanned extubations: utilization of the Penn State Children's Hospital Sedation Algorithm.
OBJECTIVE: To determine whether institution of a standardized algorithm of goal-directed sedation impacted the incidence of unplanned extubations in critically ill pediatric patients. DESIGN: Prospective, observational study with historical controls. SETTING: Pediatric intensive care unit (PICU) in a tertiary care university-based children's hospital. PATIENTS: All mechanically ventilated children admitted to the PICU during a 10-yr period. INTERVENTIONS: After examining the data pertaining to unplanned extubations, the Penn State Children's Hospital Sedation Algorithm (PSCHSA) was instituted as an absolute requirement for all mechanically ventilated children. Physician orders for the goal sedation level and the appropriate medications to achieve that goal were obligatory for every ventilated patient. Data were then collected for 5 yrs after institution of the PSCHSA. MEASUREMENTS AND MAIN RESULTS: Before utilization of the PSCHSA, unplanned extubation rates ranged between 0.44 and 0.63 per 100 intubated patient days. In the 4 yrs after mandatory use of the PSCHSA for management of all ventilated patients, unplanned extubation rates were between 0 and 0.19 per 100 intubated patient days, demonstrating a significant decrease (p<.001). Throughout the entire study period, no changes were made in the model of patient care that would alter the rate of unplanned extubations. Despite a higher percentage of PICU patients that were intubated, length of stay in the PICU did not increase, suggesting that oversedation did not led to increased ventilator days. CONCLUSIONS: Utilization of the PSCHSA resulted in a decreased number of unplanned extubations without increasing the length of PICU stay. Implementation of the PSCHSA is needed in other PICUs to validate these findings.
Algorithms↗