Citations

Abstract Rationale Transfusion-related pulmonary complications are leading causes of morbidity and mortality attributed to transfusion. Observational studies suggest an important role for red blood cell (RBC) storage duration in these adverse outcomes. Objectives To evaluate the impact of RBC storage duration on short-term pulmonary function as well as immunologic and coagulation status in mechanically ventilated patients receiving RBC transfusion. Methods This is a double-blind, randomized, clinical trial comparing fresh (≤5 d of storage) versus standard issue single-unit RBC transfusion in adult intubated and mechanically ventilated patients. The primary outcome is the change in pulmonary gas exchange as assessed by the partial pressure of arterial oxygen to fraction of inspired oxygen concentration ratio (ΔPaO2/FiO2). Secondary outcomes include changes in immune and coagulation status. Measurements and Main Results Fifty patients were randomized to receive fresh RBCs and an additional 50 patients to standard issue RBCs. Median storage age was 4.0 days (interquartile range, 3.0–5.0) and 26.5 days (interquartile range, 21.0–36.0) in the fresh RBC group and standard issue RBC group, respectively. No differences were noted in the primary outcome of ΔPaO2/FiO2 (difference between the mean ΔPaO2/FiO2 in the standard issue RBC group vs. the fresh RBC group, –11.5; 95% confidence interval, −35.3 to 12.3; P = 0.22). Similarly, no significant differences were noted in markers of immunologic or coagulation status. Conclusions In this randomized clinical trial, no differences were noted in early measures of pulmonary function or in immunologic or coagulation status when comparing fresh versus standard issue single-unit RBC transfusion. Clinical trial registered with ClinicalTrials.gov (NCT00751322).

The severity of preoperative cerebral palsy appears to correlate directly with postoperative complications. The primary aim of this study was to characterize the frequency of perioperative morbidity and mortality in cerebral palsy patients undergoing anesthesia. This was accomplished by undertaking a systematic review of the Mayo Database. The risk for perioperative adverse events was 63.1% (95% confidence interval 59.8%-66.5%). However, it deserves clarification that hypothermia and clinically significant yet non–life-threatening hypotension represented the majority (80%) of these complications. When these 2 events are excluded, the rate of adverse perioperative events was 13.1% (95% confidence interval 10.8%-15.5%). Risk factors associated with increased risk included American Society of Anesthesiologists physical status score exceeding 2, history of seizures, upper airway hypotonia, general surgery procedures, and adults. Our findings are useful to counsel patients with cerebral palsy, their caregivers, and their guardians regarding the risk of general anesthesia.

AbstractGene‐set analyses have been widely used in gene expression studies, and some of the developed methods have been extended to genome wide association studies (GWAS). Yet, complications due to linkage disequilibrium (LD) among single nucleotide polymorphisms (SNPs), and variable numbers of SNPs per gene and genes per gene‐set, have plagued current approaches, often leading to ad hoc “fixes.” To overcome some of the current limitations, we developed a general approach to scan GWAS SNP data for both gene‐level and gene‐set analyses, building on score statistics for generalized linear models, and taking advantage of the directed acyclic graph structure of the gene ontology when creating gene‐sets. However, other types of gene‐set structures can be used, such as the popular Kyoto Encyclopedia of Genes and Genomes (KEGG). Our approach combines SNPs into genes, and genes into gene‐sets, but assures that positive and negative effects of genes on a trait do not cancel. To control for multiple testing of many gene‐sets, we use an efficient computational strategy that accounts for LD and provides accurate step‐down adjustedP‐values for each gene‐set. Application of our methods to two different GWAS provide guidance on the potential strengths and weaknesses of our proposed gene‐set analyses.

AbstractBackgroundCholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts (MFBs).MFB‐derivedPDGF‐BBsurvival signalling is a mediator ofCCAcell resistance to apoptotic stimuli. This raises the concept that targetingPDGFR‐β, a cognate receptor ofPDGF‐BB, represents a potential strategy for the treatment of humanCCA.AimsHerein, we examine a role for inhibitingPDGFR‐β in restoringCCAcell sensitivity to apoptotic stimuliin vitroandin vivo.MethodsWe employed humanCCAsamples from 41 patients (19 intrahepatic and 22 extrahepaticCCAsamples), the humanCCAcell linesKMCH‐1 andHUCCT‐1 as well as shPDGFR‐β‐KMCH‐1 and human myofibroblasticLX‐2 cells for these studies.In vivo‐experiments were conducted using a syngeneic rat orthotopicCCAmodel.ResultsOf severalMFB‐derived growth factors profiled,PDGF‐BBandCTGFwere most abundantly expressed; however, onlyPDGF‐BBattenuated tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) cytotoxicity. Co‐culturingCCAcells withPDGF‐BB‐secretingMFBs significantly decreasedTRAIL‐inducedCCAcell apoptosis when compared with monoculture conditions; this cytoprotective effect was abrogated in the presence of the tyrosine kinase inhibitors imatinib mesylate or linifanib, which inhibitPDGFR‐β. Consistent with these findings,MFB‐imparted cytoprotection also was abolished whenPDGFR‐β was knocked down as demonstrated in shPDGFR‐β‐KMCH‐1 cells. Finally, administration of imatinib mesylate increasedCCAcell apoptosis and reduced tumour growth in a rodentin vivo‐CCAmodel that mimics the human disease.ConclusionsTargetingPDGFR‐β sensitizesCCAcells to apoptotic stimuli and appears to be therapeuticin vivo.

AbstractTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti–human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

Background— Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. Methods and Results— We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m 2 , respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts ( P =0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P =0.087) and lower brain natriuretic peptide ( P =0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Conclusion— Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00370214.

ABSTRACT Purpose. To determine whether treatment of symptomatic convergence insufficiency (CI) has an effect on Academic Behavior Survey (ABS) scores. Methods. The ABS is a six‐item survey developed by the Convergence Insufficiency Treatment Trial Group that quantifies the frequency of adverse school behaviors and parental concern about school performance on an ordinal scale from 0 (never) to 4 (always) with total scores ranging from 0 to 24. The ABS was administered at baseline and after 12 weeks of treatment to the parents of 218 children aged 9 to 17 years with symptomatic CI, who were enrolled in the Convergence Insufficiency Treatment Trial and randomized into (1) home‐based pencil push‐ups; (2) home‐based computer vergence/accommodative therapy and pencil push‐ups; (3) office‐based vergence/accommodative therapy with home reinforcement; and (4) office‐based placebo therapy with home reinforcement. Participants were classified as successful (n = 42), improved (n = 60), or non‐responder (n = 116) at the completion of 12 weeks of treatment using a composite measure of the symptom score, nearpoint of convergence, and positive fusional vergence. Analysis of covariance methods were used to compare the mean change in ABS between response to treatment groups while controlling for the ABS score at baseline. Results. The mean ABS score for the entire group at baseline was 12.85 (SD = 6.3). The mean ABS score decreased (improved) in those categorized as successful, improved, and non‐responder by 4.0, 2.9, and 1.3 points, respectively. The improvement in the ABS score was significantly related to treatment outcome (p < 0.0001), with the ABS score being significantly lower (better) for children who were successful or improved after treatment as compared to children who were non‐responders (p = 0.002 and 0.043, respectively). Conclusions. A successful or improved outcome after CI treatment was associated with a reduction in the frequency of adverse academic behaviors and parental concern associated with reading and school work as reported by parents.