Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM.

Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.

Computed Tomography with Intravenous Contrast Is Not Associated with Development of Acute Kidney Injury in Severely Injured Pediatric Patients.

Data for the incidence of acute kidney injury (AKI) related to intravenous contrast administration in the pediatric trauma population are limited. Obtaining a creatinine value before elective CT scans is a relatively accepted standard of care. We sought to determine whether there was any significant difference in the incidence of AKI between severely injured patients who received IV contrast and those who did not. We reviewed data from the trauma registry at our Level I pediatric trauma center. We limited the patients to severely injured pediatric traumas (<15 years old) directly transported from the scene of injury with a creatinine level measured on arrival. Two hundred and eleven patients were included in the study. AKI was defined by the criteria of the AKI Network. We then compared incidence of AKI in those who received a CT scan with IV contrast with those who did not receive IV contrast. The two groups were comparable in age, gender, Glasgow Coma Scale, Injury Severity Score, mean creatinine on arrival, and mean creatinine post-CT scan/arrival. There was no significant difference in AKI between the two. In a subgroup analysis of patients presenting in shock, there was no significant difference in AKI. Our study suggests that IV contrast is not associated with the development of AKI in severely injured pediatric trauma patients. Although obtaining a creatinine value before exposure is ideal, a CT scan with IV contrast in severely injured children should not be delayed to obtain a creatinine value.

Negative Focused Abdominal Sonography for Trauma examination predicts successful nonoperative management in pediatric solid organ injury: A prospective Arizona-Texas-Oklahoma-Memphis-Arkansas + Consortium study.

BACKGROUND: Focused Abdominal Sonography for Trauma (FAST) examination has long been proven useful in the management of adult trauma patients, however, its utility in pediatric trauma patients is not as proven. Our goal was to evaluate the utility of a FAST examination in predicting the success or failure of nonoperative management (NOM) of blunt liver and/or spleen (BLSI) in the pediatric trauma population. METHODS: A retrospective analysis of a prospective observational study of patients younger than 18 years presenting with BLSI to one of ten Level I pediatric trauma centers between April 2013 and January 2016. 1,008 patients were enrolled and 292 had a FAST examination recorded. We analyzed failure of NOM of BLSI in the pediatric trauma population. We then compared FAST examination alone or in combination with the pediatric age adjusted shock index (SIPA) as it relates to success of NOM of BLSI. RESULTS: Focused Abdominal Sonography for Trauma examination had a negative predictive value (NPV) of 97% and positive predictive value (PPV) of 13%. The odds ratio of failing with a positive FAST examination was 4.9 and with a negative FAST was 0.20. When combined with SIPA, a positive FAST examination and SIPA had a PPV of 17%, and an odds ratio for failure of 4.9. The combination of negative FAST and SIPA had an NPV of 96%, and the odds ratio for failure was 0.20. CONCLUSION: Negative FAST is predictive of successful NOM of BLSI. The addition of a positive or negative SIPA score did not affect the PPV or NPV significantly. Focused Abdominal Sonography for Trauma examination may be useful clinically in determining which patients are not at risk for failure of NOM of BLSI and do not require monitoring in an intensive care setting. LEVEL OF EVIDENCE: Prognostic study, level IV; therapeutic/care management, level IV.

Prospective validation of the shock index pediatric-adjusted (SIPA) in blunt liver and spleen trauma: An ATOMAC+ study.

BACKGROUND: Age-adjusted pediatric shock index (SIPA) does not require knowledge of age-adjusted blood pressure norms, yet correlates with mortality, serious injury, and need for transfusion in trauma. No prospective studies support its validity. METHODS: A multicenter prospective observational study of patients 4-16years presenting April 2013-January 2016 with blunt liver and/or spleen injury (BLSI). SIPA (maximum heart rate/minimum systolic blood pressure) thresholds of >1.22, >1.0, and >0.9 in the emergency department were used for 4-6, 7-12 and 13-16year-olds, respectively. Patients with ISS ≤15 were excluded to conform to the original paper. Discrimination outcomes were compared between SIPA and shock index (SI). RESULTS: Of 1008 patients, 386 met inclusion. SI was elevated in 321, and SIPA elevated in 282. The percentage of patients with elevated index (SI or SIPA) and blood transfusion within 24 hours (30% vs 34%), BLSI grade ≥3 requiring transfusion (28% vs 32%), operative intervention (14% vs 16%) and ICU admission (64% vs 67%) was higher in the SIPA group. CONCLUSION: SIPA was validated in this multi-institutional prospective study and identified a higher percentage of children requiring additional resources than SI in BLSI patients. SIPA may be useful for determining necessary resources for injured patients with BLSI. LEVEL OF EVIDENCE: Level II prognosis.

The impact of morbid obesity on solid organ injury in children using the ATOMAC protocol at a pediatric level I trauma center.

INTRODUCTION: Obesity is an epidemic in the pediatric population. Childhood obesity in trauma has been associated with increased incidence of long-bone fractures, longer ICU stays, and decreased closed head injuries. We investigated for differences in the likelihood of failure of non-operative management (NOM), and injury grade using a subset of a multi-institutional, prospective database of pediatric patients with solid organ injury (SOI). METHODS: We prospectively collected data on all pediatric patients (<18years) admitted for liver or splenic injury from September 2013 to January 2016. SOI was managed based upon the ATOMAC protocol. Obesity status was derived using CDC definitions; patients were categorized as non-obese (BMI <95th percentile) or obese (BMI ≥95th percentile). The ISS, injury grade, and NOM failure rate were calculated among other data points. RESULTS: Of 1012 patients enrolled, 117 were identified as having data regarding BMI. Eighty-four percent of patients were non-obese; 16% were obese. The groups did not differ by age, sex, mechanism of injury, or associated injuries. There was no significant difference in the rate of failure of non-operative management (8.2% versus 5.3%). Obesity was associated with higher likelihood of severe (grade 4 or 5) hepatic injury (36.8% versus 15.3%, P=0.048) but not a significant difference in likelihood of severe (grade 4 or 5) splenic injury (15.3% versus 10.5%, P=0.736). Obese patients had a higher mean ISS (22.5 versus 16.1, P=0.021) and mean abdominal AIS (3.5 versus 2.9, P=0.024). CONCLUSION: Obesity is a risk factor for more severe abdominal injury, specifically liver injury, but without an associated increase in failure of NOM. This may be explained by the presence of hepatic steatosis making the liver more vulnerable to injury. A protocol based upon physiologic parameters was associated with a low rate of failure regardless of the pediatric obesity status. LEVEL OF EVIDENCE: Level II prognosis.

Hypoalbuminemia at admission is associated with increased incidence of in-hospital complications in geriatric trauma patients.

BACKGROUND: Elderly patients are at an increased risk of protein-energy malnutrition (PEM) which increases the risk of morbidity/mortality. We evaluated the association between hypoalbuminemia at the time of emergency department (ED) admission and in-hospital complications among geriatric trauma patients. METHODS: This was an ambidirectional cohort study of geriatric (≥55 years) trauma patients treated at a Level I trauma center between May 2013 and March 2014. The exposure of interest was albumin level at ED admission (<3.6 g/dL [PEM] or ≥3.6 g/dL (No PEM)]. The outcome of interest was 30-day incidence of complications. RESULTS: A total of 130 patients met study eligibility. Of these, 85 (65%) patients were in the PEM group. After adjusting for tube feeding and injury severity score, PEM at admission was associated with a 2-fold increase in the risk of 30-day overall hospital complications (hazard ratio 2.1, 95% confidence interval 1.1 to 3.8). CONCLUSION: Serum albumin level at ED admission, but not prealbumin level, is a significant predictor of in-hospital complications in geriatric trauma patients.

Evaluating Coding Accuracy in General Surgery Residents' Accreditation Council for Graduate Medical Education Procedural Case Logs.

INTRODUCTION: The Accreditation Council for Graduate Medical Education (ACGME) case log captures resident operative experience based on Current Procedural Terminology (CPT) codes and is used to track operative experience during residency. With increasing emphasis on resident operative experiences, coding is more important than ever. It has been shown in other surgical specialties at similar institutions that the residents' ACGME case log may not accurately reflect their operative experience. What barriers may influence this remains unclear. As the only objective measure of resident operative experience, an accurate case log is paramount in representing one's operative experience. This study aims to determine the accuracy of procedural coding by general surgical residents at a single institution. METHODS: Data were collected from 2 consecutive graduating classes of surgical residents' ACGME case logs from 2008 to 2014. A total of 5799 entries from 7 residents were collected. The CPT codes entered by residents were compared to departmental billing records submitted by the attending surgeon for each procedure. Assigned CPT codes by institutional American Academy of Professional Coders certified abstract coders were considered the "gold standard." A total of 4356 (75.12%) of 5799 entries were identified in billing records. Excel 2010 and SAS 9.3 were used for analysis. In the event of multiple codes for the same patient, any match between resident codes and billing record codes was considered a "correct" entry. A 4-question survey was distributed to all current general surgical residents at our institution for feedback on coding habits, limitations to accurate coding, and opinions on ACGME case log representation of their operative experience. RESULTS: All 7 residents had a low percentage of correctly entered CPT codes. The overall accuracy proportion for all residents was 52.82% (range: 43.32%-60.07%). Only 1 resident showed significant improvement in accuracy during his/her training (p = 0.0043). The survey response rate was 100%. Survey results indicated that inability to find the precise code within the ACGME search interface and unfamiliarity with available CPT codes were by far the most common perceived barriers to accuracy. Survey results also indicated that most residents (74%) believe that they code accurately most of the time and agree that their case log would accurately represent their operative experience (66.6%). CONCLUSION: This is the first study to evaluate correctness of residents' ACGME case logs in general surgery. The degree of inaccuracy found here necessitates further investigation into the etiology of these discrepancies. Instruction on coding practices should also benefit the residents after graduation. Optimizing communication among attendings and residents, improving ACGME coding search interface, and implementing consistent coding practices could improve accuracy giving a more realistic view of residents' operative experience.

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

Immediate versus delayed repair of destructive bowel injuries in patients with an open abdomen.

Trauma surgeons frequently encounter destructive bowel injuries. The timing of the repair of the bowel injury should be performed in patients with planned open abdomen management and second-look laparotomy has not been specifically addressed. Our primary objective was to determine if there was a significant difference in the incidence of major complications between immediate and delayed repair among patients with traumatic bowel injuries and planned open abdomens. This was a retrospective cohort study of adult patients with traumatic bowel injuries treated between 2001 and 2011 and who underwent laparotomy and were left with an open abdomen with a planned second operation. Pediatric patients (age less than 15 years) and patients who died in the first 24 hours of admission were excluded. The primary exposure of interest was dichotomously defined based on either definitive repair of the bowel injury during the initial trauma operation (immediate) or definitive repair during a subsequent surgery (delayed). Major complications were defined as enterocutaneous fistula, dehiscence, and abscess. Ninety-two patients met study eligibility. Of these, 50 (54%) underwent immediate bowel repair. Univariate analysis suggested no significant differences in the proportion of major complications between the two groups. After adjusting for Injury Severity Score, penetrating injury, initial base deficit, and presence of colon injury, there was no statistical difference in incidence of major complications between the two groups. Patients undergoing immediate Versus delayed repair of traumatic bowel injuries and who are left with an open abdomen have comparable outcomes in terms of major complications.

Evaluation of SLE Susceptibility Genes in Malaysians.

Systemic Lupus Erythematosus (SLE) is a clinically heterogeneous autoimmune disease with strong genetic and environmental components. Our objective was to replicate 25 recently identified SLE susceptibility genes in two distinct populations (Chinese (CH) and Malays (MA)) from Malaysia. We genotyped 347 SLE cases and 356 controls (CH and MA) using the ImmunoChip array and performed an admixture corrected case-control association analysis. Associated genes were grouped into five immune-related pathways. While CH were largely homogenous, MA had three ancestry components (average 82.3% Asian, 14.5% European, and 3.2% African). Ancestry proportions were significantly different between cases and controls in MA. We identified 22 genes with at least one associated SNP (P < 0.05). The strongest signal was at HLA-DRA (P Meta = 9.96 × 10(-9); P CH = 6.57 × 10(-8), P MA = 6.73 × 10(-3)); the strongest non-HLA signal occurred at STAT4 (P Meta = 1.67 × 10(-7); P CH = 2.88 × 10(-6), P MA = 2.99 × 10(-3)). Most of these genes were associated with B- and T-cell function and signaling pathways. Our exploratory study using high-density fine-mapping suggests that most of the established SLE genes are also associated in the major ethnicities of Malaysia. However, these novel SNPs showed stronger association in these Asian populations than with the SNPs reported in previous studies.