Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high risk locus in patients with diabetic macular edema.

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p<5x10-8). The strongest association was rs2239785, (K150E) in APOL1. The second finding was rs10402468, which co-localized to PLVAP and ANKLE1 in vascular / endothelium tissues. We conducted multiple sensitivity analyses to establish that the associations were specific to DME status and did not reflect diabetes status or other diabetic complications. Here we report two novel loci for risk of DME which replicated in multiple clinical trial and biobank derived datasets. One of these loci, containing the gene APOL1, is a risk factor in African American DME and DKD patients, indicating that this locus plays a broader role in diabetic complications for multiple ancestries. Trial Registration: NCT00473330, NCT00473382, NCT03622580, NCT03622593, NCT04108156.

Screening for Bacteremia in Trauma Patients: Traditional Markers Fall Short.

BACKGROUND: Deranged physiology in trauma complicates the clinical identification of sepsis, resulting in overscreening for bacteremia. No clinical signs or biomarkers accurately diagnose sepsis in this population. Our objective was to evaluate the accuracy of the current criteria used to prompt screening for bacteremia in trauma patients and determine independent predictors of bacteremia. MATERIALS AND METHODS: Adult trauma patients admitted to our level I academic trauma center who had blood cultures (BCs) drawn were identified. Those with positive BCs were compared to those with negative or false positive BCs. False positive was defined as a BC deemed contaminated and not treated at the discretion of the attending physician. RESULTS: Over a 2-year period, 366 trauma patients had BCs drawn. After excluding surveillance cultures (those drawn to demonstrate bacteremia clearance), 492 unique BC sets were evaluated; 104 (21.1%) BC sets were positive; 30 (28.8%) of these were falsely positive, resulting in a true-positive rate of 15% in the screened population. Univariate analysis suggested temperature and heart rate were associated with positive BC, while multivariable analysis found only the presence of a central line and lactic acid to be predictive. Procalcitonin (PCT) was poorly predictive, with a positive predictive value of 18% and a negative predictive value of 91%. CONCLUSION: Current tools for identifying bacteremia in trauma patients result in overscreening. PCT may have a limited role as a negative predictor for bacteremia. Given that false-positive BCs have negative patient and economic consequences, future study should focus on development of alternative screening modalities.

Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy.

Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by ß-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.

The Golden Opportunity: Multidisciplinary Simulation Training Improves Trauma Team Efficiency.

OBJECTIVE: Every trauma patient has a golden hour, and resuscitation efficiency within that hour has large implications for patients. We instituted simulation based trauma resuscitation training with the hypothesis that it would improve trauma team efficiency. METHODS: Five simulation training sessions were conducted with immediate debriefing. Metrics collected in actual trauma resuscitations before and after simulation training included time of primary and secondary surveys and time to computed tomography (CT) scan. Study participants were from multidisciplinary specialties involved in trauma resuscitations as well as former trauma patients from the Trauma Survivors Network. RESULTS: Seventy-three patients undergoing trauma resuscitations were screened and 67 patients were included. Time to CT scan and secondary survey completion were significantly reduced in actual trauma patient activations following implementation of the curriculum (reduction of 23 to 16 minutes for CT scan p < 0.05, and reduction from 14 to 6 minutes for secondary survey, p < 0.05). Time to primary survey completion did not change (5 minutes). CONCLUSIONS: Multidisciplinary simulation training was associated with improved trauma team efficiency in the form of reduced assessment time. As emergency department length of stay is an independent predictor of hospital mortality following trauma activation, team-based simulation training has the potential to improve patient outcomes. Multidisciplinary involvement was a key factor, and Trauma Survivors Network involvement brought credibility from the patient perspective.

Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.

Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN, we discovered multiple lines of evidence that PGRN deficiency results in impairment of autophagy, a key cellular degradation pathway. PGRN-deficient mice are sensitive to Listeria monocytogenes because of deficits in xenophagy, a specialized form of autophagy that mediates clearance of intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and pathological forms of TDP-43 typically cleared by autophagy accumulate more rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel therapeutic target for GRN-associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease.

Damage control operations in non-trauma patients: defining criteria for the staged rapid source control laparotomy in emergency general surgery.

BACKGROUND: The staged laparotomy in the operative management of emergency general surgery (EGS) patients is an extension of trauma surgeons operating on this population. Indications for its application, however, are not well defined, and are currently based on the lethal triad used in physiologically-decompensated trauma patients. This study sought to determine the acute indications for the staged, rapid source control laparotomy (RSCL) in EGS patients. METHODS: All EGS patients undergoing emergent staged RSCL and non-RSCL over 3 years were studied. Demographics, physiologic parameters, perioperative variables, outcomes, and survival were compared. Logistic regression models determined the influence of physiologic parameters on mortality and postoperative complications. EGS-RSCL indications were defined. RESULTS: 215 EGS patients underwent emergent laparotomy; 53 (25 %) were staged RSCL. In the 53 patients who underwent a staged RSCL based on the lethal triad, adjusted multivariable regression analysis shows that when used alone, no component of the lethal triad independently improved survival. Staged RSCL may decrease mortality in patients with preoperative severe sepsis / septic shock, and an elevated lactate (≥3); acidosis (pH ≤ 7.25); elderly (≥70); male gender; and multiple comorbidities (≥3). Of the 162 non-RSCL emergent laparotomies, 27 (17 %) required unplanned re-explorations; of these, 17 (63 %) had sepsis preoperatively and 9 (33 %) died. CONCLUSIONS: The acute physiologic indicators that help guide operative decisions in trauma may not confer a similar survival advantage in EGS. To replace the lethal triad, criteria for application of the staged RSCL in EGS need to be defined. Based on these results, the indications should include severe sepsis / septic shock, lactate, acidosis, gender, age, and pre-existing comorbidities. When correctly applied, the staged RSCL may help to improve survival in decompensated EGS patients.

Subcapsular hematoma in blunt splenic injury: A significant predictor of failure of nonoperative management.

BACKGROUND: In patients with blunt splenic injury (BSI), patient selection, angiography, and embolization have contributed to low nonoperative management (NOM) failure rates. Despite these advances, some patients will fail NOM. We noted that a significant proportion of NOM failures had subcapsular hematomas (SCHs) identified on imaging. We sought to determine if there is a correlation between SCH and higher risk of NOM failure after BSI. METHODS: Our institutional trauma registry was queried for all patients with BSI during a 2-year period. Charts were reviewed to determine grade, presence of SCH, and outcome of NOM. Under current institutional protocol, all stable patients with BSI Grades III to V and those with contrast blush on computed tomography are referred for angiography and embolization. Failure of NOM was declared if splenectomy was required for bleeding after an initial plan of nonoperation. RESULTS: From May 2012 to May 2014, 312 patients with BSI were identified. A total of 253 patients (81%) underwent NOM. Overall, 15 (5.9%) failed NOM. Of those undergoing NOM, 34 had SCH and 12 failed (35.3% vs. 1.5% without SCH, p = 0.0001). Failure rates in Grades 1 to 4 were 2.3%, 3.8%, 8.8%, and 19.2%, respectively. NOM failure rates in the subset with SCH for Grades I to IV were 20%, 25%, 30.8%, and 80%, respectively. These are significantly higher than patients without SCH in Grades II to IV (0%, p = 0.003; 2.3%, p = 0.008; and 4.8%, p = 0.016) and approach significance in Grade I (1.2%, p = 0.11). There were no SCHs and no failures of NOM in Grade V injuries. CONCLUSION: The NOM failure rate of BSI patients with SCH is significantly higher than those without SCH. Patients with BSI Grades I to III slated for NOM must be observed as the failure rate approaches 30%. Splenectomy should be considered in patients with Grade IV BSI with SCH, as NOM failure rate is 80%. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Effect of aging on cardiac function plus monitoring and support.

Cardiovascular disease is the most prevalent and influential comorbidity affecting outcomes in geriatric surgical patients. The unique physiology of the aging cardiovascular system and the impact of these changes during the stress of surgery is presented in this article. The necessary response to these changes is discussed with attention to methods of monitoring and recommendations for providing supportive care.

Stapled versus hand-sewn anastomoses in emergency general surgery: a retrospective review of outcomes in a unique patient population.

BACKGROUND: Recent studies have identified unique clinical and physiologic characteristics of emergency general surgery (EGS) patients and called for outcomes data in this population. There are no data in the US literature analyzing the impact of technique on anastomotic failure rates in EGS patients. The purpose of the current study was to compare outcomes of hand-sewn (HS) versus stapled (ST) bowel anastomoses in EGS patients. METHODS: A retrospective chart review of all patients admitted by our EGS service undergoing bowel resection for emergent indications from January 2007 to July 2011 was performed. Time from surgery to diagnosis of anastomotic failure was recorded as were the diagnostic modality and treatment of each anastomotic failure. Specific data on damage-control techniques, if used, were also collected. RESULTS: There were 100 HS (43%), and 133 ST (57%) anastomoses in 231 patients. Operative times were shorter in ST anastomosis technique (205 minutes for HS vs. 193 minutes for ST, p = 0.02). Anastomotic failures were identified in 26 patients (11%) and were significantly higher in the ST group than the HS group (15.0% vs. 6.1%, p = 0.003). A multivariate logistic regression analysis, controlling for age and preoperative nutritional status, revealed ST technique to be an independent risk factor for anastomotic failure (odds ratio, 2.65; 95% confidence interval, 1.08-6.50; p = 0.034). CONCLUSION: Anastomotic failures are more than twice as likely with ST than HS anastomoses in the EGS population. This is true even when controlling for markers of preoperative nutrition and demographics. These data suggest that the HS anastomosis should be the preferred method of reconstruction after bowel resection in EGS patients.

Systemic inflammation worsens outcomes in emergency surgical patients.

BACKGROUND: Acute care surgeons are uniquely aware of the importance of systemic inflammatory response and its influence on postoperative outcomes; concepts like damage control have evolved from this experience. For surgeons whose practice is mostly elective, the significance of such systemic inflammation may be underappreciated. This study sought to determine the influence of preoperative systemic inflammation on postoperative outcome in patients requiring emergent colon surgery. METHODS: Emergent colorectal operations were identified in the American College of Surgeons National Surgical Quality Improvement Program 2008 dataset. Four groups were defined by the presence and magnitude of the inflammatory response before operation: no inflammation, systemic inflammatory response syndrome (SIRS), sepsis, or severe sepsis/septic shock. Thirty-day survival was analyzed by Kaplan-Meier method. RESULTS: A total of 3,305 patients were identified. Thirty-day survival was significantly different (p < 0.0001) among the four groups; increasing magnitudes of preoperative inflammation had increasing probability of mortality (p < 0.0001). Hazard ratios indicated that, compared with patients without preoperative systemic inflammation, the relative risk of death from SIRS was 1.9 (p < 0.0001), from sepsis was 2.5 (p < 0.0001), and from severe sepsis/septic shock was 6.7 (p < 0.0001). Operative time of <150 minutes was associated with decreased risk of morbidity (odds ratio = 0.64; p < 0.0001). CONCLUSIONS: Upregulation of the systemic inflammatory response is the primary contributor to death in emergency surgical patients. In SIRS or sepsis patients, operations <2.5 hours are associated with fewer postoperative complications. These results further reinforce the concept of timely surgical intervention and suggest a potential role for damage control operations in emergency general surgery. LEVEL OF EVIDENCE: II, prognostic study.

Acute care surgery: impact on practice and economics of elective surgeons.

BACKGROUND: The creation of an acute care surgery service provides a rich operative experience for acute care surgeons. Elective surgeons typically have concerns about whether their practice volume will be restored with elective cases. Acute care surgery has financial implications for both groups. The aim of this project is to examine the impact in terms of work relative value units (wRVUs), collections, and cases in both groups with creation of an acute care surgery service at our institution. STUDY DESIGN: Work RVUs, collections, and case volume were examined from departmental records for 2 groups before and after acute care surgery service creation. The service began on September 1, 2008. Before this time, emergency surgical consults went to the general surgeon on call. After this date, all emergency consults were seen by acute care surgeons. RESULTS: The number of operations performed by the acute care surgery group increased significantly when the mean of the 2 years after institution of acute care surgery were compared with the mean of the 2 years preceding the service creation (1,639 vs 790/year; p = 0.007). There was no change in total operations done by the elective surgery group (2,763 vs 2,496/year: p = 0.13). Elective caseload, however, did increase by 23% in the elective surgery group. In the acute care surgery group, wRVUs increased by 140% and elective surgery group wRVUs decreased by 8%. Collections increased in both groups (acute care surgery 129%, elective surgery 7%) and the combined collections of the groups increased by $2,138,00 in the year after service creation. CONCLUSIONS: Acute care surgery service creation took emergency business from the elective surgery group, but this was almost immediately replaced with elective cases. This resulted in higher collections for both groups and a resultant significant increase in collections in aggregate.

Creation and implementation of an emergency general surgery registry modeled after the National Trauma Data Bank.

BACKGROUND: As emergency general surgery (EGS) evolves, an EGS patient-tracking database (EGS registry [EGSR]) similar to the National Trauma Data Bank (NTDB) will be essential to study outcomes and improve care. The goal of this study was to establish diagnostic ICD-9 codes to define EGS patients. The hypothesis was that creating standardized ICD-9-based inclusion criteria would facilitate patient identification for an EGSR and aid in its ongoing development. STUDY DESIGN: We conducted a retrospective review of EGS admissions over a 9-month period to define ICD-9 diagnostic codes of patients admitted to our EGS service. Subsequently, prospective data were collected into the EGSR by testing ICD-9-based inclusion criteria over 1 month. Patient, hospital, and severity scoring variables, as well as quality assurance information, were identified. RESULTS: We identified 959 admissions to the EGS service over 9 months with 306 ICD-9 diagnosis codes that define EGS patients; the prospective population of the EGSR confirmed feasibility of ICD-9-based inclusion criteria. The EGSR captures 107 data points and 33 comorbidities per patient over 11 categories, akin to the 10 NTDB categories. CONCLUSIONS: Following the model of the NTDB, we have successfully completed creation and initial implementation of an EGSR by using ICD-9-based inclusion criteria. Our comprehensive EGSR creates a prospective data-collection modality to capture and define EGS patients. A uniform patient-tracking EGSR, akin to the NTDB, will advance the science of acute care surgery, improve EGS patient outcomes, and facilitate multi-institutional collaboration.

A critical assessment of outcomes in emergency versus nonemergency general surgery using the American College of Surgeons National Surgical Quality Improvement Program database.

Emergent operations are thought to carry higher morbidity and mortality than nonemergent cases. However, there is a lack of specific outcomes data for emergent general surgery procedures. The objective of our study was to assess and quantify postoperative morbidity and mortality for emergency versus nonemergency general surgery operations. All general surgery inpatients were identified in the American College of Surgeons National Surgical Quality Improvement Program 2008 database. Preoperative, intraoperative, and postoperative clinical metrics and occurrences were assessed. A total of 25,770 emergent and 98,867 nonemergent cases were identified. Postoperative morbidity was significantly worse in the emergent group, including ventilation more than 48 hours, bleeding requiring transfusion, deep vein thrombosis, renal failure, and need for reoperation. Overall, emergent cases had significantly more postoperative complications (22.8% vs 14.2%) and higher mortality rates (6.5% vs 1.4%). General surgery patients who undergo emergent operations have significantly poorer outcomes when compared with nonemergent patients; our analysis has quantified these differences. Emergent patients seem to manifest unique clinical, pathophysiologic, and inflammatory responses to their surgical disease. This data suggests that there is a need for improvement in both methods and systems of care for the emergent population.

Vacuum-assisted closure for defects of the abdominal wall.

BACKGROUND: Reconstruction of the abdominal wall poses a problem common to many surgical specialties. Abdominal wall defects may be caused by trauma and/or prior surgery, with dehiscence or infection. Several options to repair the structural integrity of the abdominal wall exist, including primary closure, flaps, mesh, and skin grafts. Complications of these procedures include recurrent infection of the abdominal wall, infection of mesh, dehiscence, flap death, and poor skin graft take. Risk factors predisposing to these complications include tissue edema, preoperative tissue infection, and patient debilitation, with poor wound healing potential. Ideally, reconstruction should be performed on a nonedematous, clean tissue bed with bacterial levels less than 10 bacteria/cm in a well-nourished patient. METHODS: Vacuum-assisted closure was used in a series of patients in an attempt to prepare the abdominal wall for reconstruction and reduce the risk of complications. Charts were reviewed for 100 patients who underwent abdominal wall reconstruction after vacuum-assisted closure therapy. Their wound cause, reconstruction technique, complications, and number of days on the vacuum-assisted closure device are reported. RESULTS: The ability of vacuum-assisted closure to reduce edema, increase blood flow, potentially decrease bacterial colonization, and reduce wound size greatly facilitated abdominal wall reconstruction. The vacuum-assisted closure device served as a temporary dressing with which to control dehiscence and to maintain abdominal wall integrity when bowel wall edema prevented abdominal closure. CONCLUSION: Vacuum-assisted closure therapy frequently shortened time to abdominal wall reconstruction and simplified the method of reconstruction.

Colonic resection in the setting of damage control laparotomy: is delayed anastomosis safe?

Based on a large body of literature concerning the subject, trauma surgeons are becoming more comfortable with anastomosis rather than stoma creation in patients with destructive colon injuries requiring resection. This literature was largely generated before the widespread acceptance of the importance of damage control laparotomy (DCL). Thus, when such injuries occur in patients initially left in colonic discontinuity after DCL, the question of anastomosis versus stoma becomes more difficult, and there are no data to guide management decisions. The goal of this report is to describe the results of our early experience with delayed anastomosis (DA) after destructive colon injury in the setting of DCL. We reviewed the records of patients with destructive colon injuries at our Level I trauma center over a 5.5-year period for demographics, injury characteristics, and outcome. Studied outcomes included anastomotic leak, intra-abdominal abscess, and colon injury-related death. The decision to proceed with DA was based on individual surgeon opinion at the time of re-exploration. From January 1, 2000 to July 31, 2006, 92 patients sustained colon injury, 55 of which required resection (31 blunt mechanism and 24 penetrating). Twenty-two resections occurred in the setting of DCL. Six of these patients underwent stoma creation and 11 underwent DA. Three died before reoperation, and two had an anastomosis created during the initial DCL. The remaining 33 resections occurred during initial definitive operation, and 21 underwent anastomosis, whereas 12 had a stoma created. Comparing the 11 patients undergoing DA with the 21 undergoing immediate anastomosis, the anastomotic leak rate (0% vs 5%), abscess rate (36% vs 24%), and colon related-death rate (9% vs 0%; all P > 0.05) were similar. Six patients undergoing DA had a right hemicolectomy with ileocolonic anastomosis, four had a segmental left colon resection, and one had a near total abdominal colectomy with ileosigmoid anastomosis. Delayed anastomosis of colon injuries after DCL is safe in selected patients and has a similar complication rate as resection and anastomosis performed during initial definitive operation. DA avoids stoma creation in some patients who are not candidates for anastomosis during initial DCL. To our knowledge, this represents the first reported series of DA after DCL, an area in which further work is needed to carefully define indications for the safe application of this concept.

Prospective evaluation of vacuum-assisted fascial closure after open abdomen: planned ventral hernia rate is substantially reduced.

OBJECTIVE: The goal of this report is to examine the success of vacuum-assisted fascial closure (VAFC) under a carefully applied protocol in abdominal closure after open abdomen. SUMMARY BACKGROUND DATA: With the development of damage control techniques and the understanding of abdominal compartment syndrome, the open abdomen has become commonplace in trauma patients. If the abdomen is not closed in the early postoperative period, the combination of adhesions and fascial retraction frequently make primary fascial closure impossible and creation of a planned ventral hernia is required. We have previously reported our experience with the development of a technique for VAFC that allowed for closure of the fascia in many such patients long after initial operation. During this previous study, during which the technique was being developed, VAFC was successful in 69% of patients in whom it was applied, and 22 patients were successfully closed at > or = 9 days after initial surgery (range, 9 to 49 days). A protocol for the use of VAFC in patients with open abdomen was developed on the basis of these data and has been employed since October 2001. The outcome of this protocol's use is examined. METHODS: This is a prospective evaluation of all trauma patients admitted to Wake Forest University Baptist Medical Center over a 19-month period who required management with an open abdomen. VAFC employs suction applied to a large polyurethane sponge under an occlusive dressing in the wound and allows for constant medial traction of the abdominal fascia. It is attempted in all patients in whom the rectus muscles and fascia are intact. Studied variables include fascial closure rate, time to closure, incidence of wound dehiscence, and hernia development after closure. RESULTS: From November 1, 2001, through May 31, 2003, 212 laparotomies were performed in injured patients; 53 (25%) of these patients required open abdomen management. Mean injury severity score for the group was 34, with an average abdominal abbreviated injury score of 2.9. Forty-five (78%) survived until abdominal closure. Vacuum dressings were used in all 45 but VAFC was not attempted in 2 patients (1 due to development of enterocutaneous fistula, 1 because a rectus flap was used for another wound). Closure rate in those undergoing VAFC was 88% (38), with mean time to closure being 9.5 days. This is significantly higher than the 69% rate of fascial closure during the time in which the technique was developed (P = 0.03). Twenty-one patients (48%) were closed at > or =9 days (range, 9 to 21 days). Two patients (4.6%) developed wound dehiscence and underwent successful reclosure. One patient (2.3%) developed a ventral hernia on follow-up, which has since been repaired CONCLUSIONS: The use of VAFC under a carefully defined protocol has resulted in significantly higher fascial closure rates, obviating the need for subsequent hernia repair in most patients. The utility of this technique is not limited to the early postoperative period, but it can be successful as much as 3 to 4 weeks after initial operation.