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Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
OBJECTIVES/SPECIFIC AIMS: This study aims to assess the safety, feasibility, clinical benefits and pharmacodynamics of adding allopurinol to standard maintenance therapy that includes 6-mecaptopurine (6-MP) in pediatric patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma. Our goal is to investigate if allopurinol improves hepatotoxicity and GI toxicity, if it safely decreases acute neutrophil count (ANC), if it reduces the 6-MP dose required during chemotherapy, and if it works through our hypothesized mechanism by lowering the levels of the toxic metabolite, 6-methylmecaptopurine (6-MMP) and by raising the levels of the active metabolite, 6-thioguanine (6-TGN). METHODS/STUDY POPULATION: This is a single arm, nonblinded pilot study of patients under age 30 years who were being treated in the maintenance phase of therapy for ALL or lymphoblastic lymphoma, and had adverse effects such as high 6-MMP:6-TGN ratio, high ANC, and high liver enzymes. Patients enrolled were started with allopurinol in addition to ongoing oral chemotherapy. Data from beginning maintenance to end of chemotherapy was collected in the electronic medical record, EPIC for the 13 patients enrolled at Johns Hopkins, and data analysis was conducted using STATA and Excel. RESULTS/ANTICIPATED RESULTS: Initial data analysis reveals that the required dose of 6-MP after addition of allopurinol to the chemotherapy regimen was significantly lower compared with that before the addition of allopurinol in 11 out of the 12 patients assessed (p<0.05). Among the 10 patients that were assessed for 6MMP:6TG ratio, all had lower average 6MMP:6TGN ratios after allopurinol compared to before allopurinol; the percentage of weeks that goal 6MMP:6TGN ratio (<40) were maintained were statistically significant in 6 patients (p<0.05) and close to significance in 2 other patients (p=0.057). The percentage of weeks that patients maintained alanine aminotransferase levels below 120 was significantly greater after addition of allopurinol compared to before the addition of allopurinol in 9 out of 13 patients assessed, suggesting that allopurinol may be associated with reduced hepatotoxicity. Further data analysis is ongoing to assess the percentage of weeks that patients maintained goal total bilirubin, direct bilirubin, and ANC, as well as average number of admissions for infections and average number of therapy holds after allopurinol addition compared to before allopurinol addition. DISCUSSION/SIGNIFICANCE OF IMPACT: Allopurinol is associated with reduction in required 6-MP dose, decrease in the percentage of weeks that patients have hepatotoxicity, and reduction in the ratio of toxic metabolite to active anti-leukemic metabolite in several patients. We hope that the results of this study can be used for further research and for guiding clinical practice since there are no established guidelines in pediatric oncology regarding addressing side effects of oral chemotherapy using 6-MP. If allopurinol indeed is safe and effective, adding it to the standard chemotherapy regimen can lead to better tolerance and compliance to oral maintenance chemotherapy, and hopefully improved outcomes for children with ALL and lymphoblastic leukemia.
We evaluated the collective impact of several infection prevention and control initiatives aimed at reducing acute respiratory infections (ARIs) in a pediatric long-term care facility. ARIs did not decrease overall, though the proportion of infections associated with outbreaks and average number of cases per outbreak decreased. Influenza rates decreased significantly.
A complication is an event or occurrence that is associated with a disease or a healthcare intervention, is a departure from the desired course of events, and may cause, or be associated with, suboptimal outcome. A complication does not necessarily represent a breech in the standard of care that constitutes medical negligence or medical malpractice. An operative or procedural complication is any complication, regardless of cause, occurring (1) within 30 days after surgery or intervention in or out of the hospital, or (2) after 30 days during the same hospitalization subsequent to the operation or intervention. Operative and procedural complications include both intraoperative/intraprocedural complications and postoperative/postprocedural complications in this time interval.
The MultiSocietal Database Committee for Pediatric and Congenital Heart Disease has set forth a comprehensive list of complications associated with the treatment of patients with congenital cardiac disease, related to cardiac, pulmonary, renal, haematological, infectious, neurological, gastrointestinal, and endocrinal systems, as well as those related to the management of anaesthesia and perfusion, and the transplantation of thoracic organs. The objective of this manuscript is to examine the definitions of operative morbidity as they relate specifically to a collection of loosely related topics that include the following groups of complications: 1) Complications of the Integument, 2) Complications of the Vascular System, 3) Complications of the Vascular-Line(s), 4) Complications of Wounds. These specific definitions and terms will be used to track morbidity associated with surgical and transcatheter interventions and other forms of therapy in a common language across many separate databases.
As surgical survival in children with congenital cardiac disease has improved in recent years, focus has necessarily shifted to reducing the morbidity of congenital cardiac malformations and their treatment. A comprehensive list of complications is presented. This list is a component of a systems-based compendium of complications that will standardize terminology and thereby allow the study and quantification of morbidity in patients with congenital cardiac malformations. Clinicians caring for patients with congenital cardiac disease will be able to use this list for databases, initiatives to improve quality, reporting of complications, and comparing strategies of treatment.
Early results from the SAGE-SMC (Surveying the Agents of Galaxy Evolution in the tidally-disrupted, low-metallicity Small Magellanic Cloud) Spitzer legacy program are presented. These early results concentrate on the SAGE-SMC MIPS observations of the SMC Tail region. This region is the high H i column density portion of the Magellanic Bridge adjacent to the SMC Wing. We detect infrared dust emission and measure the gas-to-dust ratio in the SMC Tail and find it similar to that of the SMC Body. In addition, we find two embedded cluster regions that are resolved into multiple sources at all MIPS wavelengths.
Low socioeconomic status (SES) background has been identified as a risk for several mental disorders. However evidence regarding SES and the developmental course of personality disorder (PD) has not been addressed. Nor is it clear whether an SES relationship to PD symptom course may be attributable to known associated risks. Further, specificity of such relationships to a particular PD diagnostic pattern independent of comorbidity with other PD or with depression has not been investigated. Data are from a general population studied longitudinally between ages 10 and 36 in four assessment waves. Effects of SES-associated risks on the level of symptoms of schizotypal and borderline disorders are estimated and compared to effects on depressive symptoms. Low family SES had robust modest independent effects on both PDs over the entire age span despite substantial cumulative effects of trauma history, stressful recent life events, IQ, poor parenting, and comorbid symptoms. SES effects on depressive symptoms were generally absent, but a small “protective” effect of low SES appeared when comorbidity with PD symptoms was taken into account. Cumulatively, these risks account for developmental failures of substantial magnitude and consequence, marking the importance of understanding the remaining mechanisms of SES effects and programmatic implications for minimizing associated risk.
The abilities for both computer technology, and intra-operative video-imaging, are evolving rapidly. The merger of these two sciences can be very beneficial, both to congenital cardiac surgeons in general, and in facilitating the creation of a cardioscopic database in particular.
Cluster A odd or eccentric personality disorder (PD) symptoms may
reflect a schizophrenia spectrum biological vulnerability in at least some
persons. Consequently, this symptom pattern may have particularly negative
effects on the transition from adolescent to adult roles. A general
population sample of 200 young adults was assessed on Cluster A PD at mean
ages 17 and 22, and subsequently provided detailed narratives about their
monthly experiences and behaviors between these two ages. Adolescent
Cluster A PD was related to the developmental trajectories of residential,
career, financial, romantic, and family formation roles during this
period, and trajectories were related to a change in symptoms over this
period. Symptoms were associated with early parenthood and less advanced
education, but for other developmental outcomes tended to differ for men
and women. These gender differences were attributable, in part, to the
differential meaning and consequences of early parenthood for men and
women.This work was funded by NIMH Grant
MH-54161 to Patricia Cohen, and by the New York State Office of Mental