Epidemiology and risk factors for fat embolism in isolated lower extremity long bone fractures.

PURPOSE: Fat embolism syndrome (FES) is a serious complication after orthopedic trauma. The aim of this study was to identify risk factors for FES in isolated lower extremity long bone fractures. METHODS: The National Trauma Data Bank "NTDB" study included patients with isolated femoral and tibial fractures. A total of 344 patients with FES were propensity score matched with 981 patients without FES. Multivariate logistical regression was used to identify independent risk factors for FES. RESULTS: FES was diagnosed in 344 (0.03%) out of the 1,251,143 patients in the study populations. In the two matched groups, the mortality was 7% in the FES group and 1% in the No FES group (p < 0.001). FES was associated with an increased risk of ARDS, VTE, pneumonia, AKI, and stroke. Younger age, femur fractures, obesity, and diabetes mellitus were independent predictors of FES. Early operative fixation (≤ 48 h) was protective against FES. CONCLUSION: FES increases mortality by seven times. Young age, obesity, and diabetes mellitus are significant independent risk factors for FES. Early fixation is independently associated with a reduced risk of FES. LEVEL OF EVIDENCE: Level III. STUDY TYPE: Prognostic study.

Injury Patterns and Treatment Strategies in Civilian and Military Isolated Abdominal Gunshot Wounds.

BACKGROUND: Combat-related gunshot wounds (GSW) may differ from those found in civilian trauma centers. Missile velocity, resources, logistics, and body armor may affect injury patterns and management strategies. This study compares injury patterns, management, and outcomes in isolated abdominal GSW between military (MIL) and civilian (CIV) populations. METHODS: The Department of Defense Trauma Registry (DoDTR) and TQIP databases were queried for patients with isolated abdominal GSW from 2013 to 2016. MIL patients were propensity score matched 1:3 based on age, sex, and extraabdominal AIS. Injury patterns and in-hospital outcomes were compared. Initial operative management strategies, including selective nonoperative management (SNOM) for isolated solid organ injuries, were also compared. RESULTS: Of the 6435 patients with isolated abdominal GSW, 183 (3%) MIL were identified and matched with 549 CIV patients. The MIL group had more hollow viscus injuries (84% vs. 66%) while the CIV group had more vascular injuries (10% vs. 21%) (p < .05 for both). Operative strategy differed, with more MIL patients undergoing exploratory laparotomy (95% vs. 82%) and colectomy (72% vs. 52%) (p < .05 for both). However, no difference in ostomy creation was appreciated. More SNOM for isolated solid organ injuries was performed in the CIV group (34.1% vs. 12.5%; p < 0.05). In-hospital outcomes, including mortality, were similar between groups. CONCLUSIONS: MIL abdominal GSW lead to higher rates of hollow viscus injuries compared to CIV GSW. MIL GSW are more frequently treated with resection but with similar ostomy creation compared to civilian GSW. SNOM of solid organ injuries is infrequently performed following MIL GSW.

Operative management and outcomes of colorectal injuries after gunshot wounds in the deployed military setting versus civilian trauma centers.

INTRODUCTION: Colon and rectal injuries have been diverted at higher rates in military trauma compared with civilian injuries. However, in the last few years, there has been a shift to more liberal primary anastomosis in wartime injuries. The purpose of this study was to compare the management and outcomes in colorectal gunshot wounds (GSWs) between military and civilian settings. METHODS: The study included Department of Defense Trauma Registry and Trauma Quality Improvement Program database patients who sustained colorectal GSWs, during the period 2013 to 2016. Department of Defense Trauma Registry patients were propensity score matched 1:3 based on age, sex, grade of colorectal injury, and extra-abdominal Abbreviated Injury Scale. Patients without signs of life, transfers from an outside hospital, and nonspecific colorectal Organ Injury Scale were excluded. Operative management and outcomes were compared between the two groups. Subanalysis was performed on the military cohort to identify any differences in the use primary repair, colectomy, or fecal diversion based upon military affiliation or North Atlantic Treaty Organization status. RESULTS: Overall, there were 2,693 patients with colorectal GSWs; 60 patients in the military group were propensity score matched with 180 patients in the civilian group. Overall, colectomy was the most common procedure performed (72.1%) and was used more frequently in the military group (83.3% vs. 68.3%; p < 0.05). However, the rate of fecal diversion was similar in the two groups (23.3% vs. 27.8%; p = 0.500). Among those in the military group, no difference was seen in primary repair, colectomy, or fecal diversion based upon military affiliation or North Atlantic Treaty Organization status. The rates of in-hospital compilations and mortality were similar between the military and civilian groups. CONCLUSION: The severity of GSW colorectal injuries in military and civilian trauma was comparable. There was no significant difference in terms of fecal diversion, mortality, and complications between groups. Military personnel are treated similarly regardless of affiliation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Bacteriophage antidefense genes that neutralize TIR and STING immune responses.

Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as an immune defense strategy to prevent the propagation of bacteriophage viruses. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to mobilize cognate death effectors. Here, we identify a family of bacteriophage nucleotidyltransferases (NTases) that synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit TIR NADase effectors activated via a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of cell suicide induced by heterologous expression of tonically active TIR-STING. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphohydrolase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a potential role for the alarmone-activated host toxin MazF as an executioner of TIR-driven Abi. Phage NTases and counterdefenses like Atd1 preserve host viability to ensure virus propagation and represent tools to modulate TIR and STING immune responses.

Therapeutic Interventions and Outcomes in Civilian and Military Isolated Gunshot Wounds to the Head: A Department of Defense Trauma Registry and ACS TQIP-matched Study.

OBJECTIVE: The purpose of this study was to compare therapeutic strategies and outcomes, following isolated gunshot wounds of the head, between military and civilian populations. BACKGROUND: Recent military conflicts introduced new concepts in trauma care, including aggressive surgical intervention in severe head trauma. METHODS: This was a cohort-matched study, using the civilian Trauma Quality Improvement Program (TQIP) database of the American College of Surgeons (ACS) and the Department of Defense Trauma Registry (DoDTR), during the period 2013 to 2016. Included in the study were patients with isolated gunshots to the head. Exclusion criteria were dead on arrival, civilians transferred from other hospitals, and patients with major extracranial associated injuries (body area Abbreviated Injury Scale >3). Patients in the military database were propensity score-matched 1:3 with patients in the civilian database. RESULTS: A total of 136 patients in the DoDTR database were matched for age, sex, year of injury, and head Abbreviated Injury Scale with 408 patients from TQIP. Utilization of blood products was significantly higher in the military population ( P <0.001). In the military group, patients were significantly more likely to have intracranial pressure monitoring (17% vs 6%, P <0.001) and more likely to undergo craniotomy or craniectomy (34% vs 13%, P <0.001) than in the civilian group. Mortality in the military population was significantly lower (27% vs 38%, P =0.013). CONCLUSIONS: Military patients are more likely to receive blood products, have intracranial pressure monitoring and undergo craniectomy or craniotomy than their civilian counterparts after isolated head gunshot wounds. Mortality is significantly lower in the military population. LEVEL OF EVIDENCE: Level III-therapeutic.

Worse outcomes with resuscitative endovascular balloon occlusion of the aorta in severe pelvic fracture: A matched cohort study.

BACKGROUND: Severe pelvic fracture is the most common indication for resuscitative endovascular balloon occlusion of the aorta (REBOA). This matched cohort study investigated outcomes with or without REBOA use in isolated severe pelvic fractures. METHODS: Trauma Quality Improvement Program database study, included patients with isolated severe pelvic fracture (AIS≥3), excluded associated injuries with AIS >3 for any region other than lower extremity. REBOA patients were propensity score matched to similar patients without REBOA. Outcomes were mortality and complications. RESULTS: 93 REBOA patients were matched with 279 without. REBOA patients had higher rates of in-hospital mortality (32.3% vs 19%, p = 0.008), higher rates of venous thromboembolism (14% vs 6.5%, p = 0.023) and DVT (11.8% vs 5.4%, p = 0.035). In multivariate analysis, REBOA use was independently associated with increased mortality and venous thromboembolism. CONCLUSIONS: REBOA in severe pelvic fractures is associated with higher rates of mortality, venous thromboembolism.

Gene-Environment Interactions for Cardiovascular Disease.

PURPOSE OF REVIEW: We provide an overview of recent findings with respect to gene-environment (GxE) interactions for cardiovascular disease (CVD) risk and discuss future opportunities for advancing the field. RECENT FINDINGS: Over the last several years, GxE interactions for CVD have mostly been identified for smoking and coronary artery disease (CAD) or related risk factors. By comparison, there is more limited evidence for GxE interactions between CVD outcomes and other exposures, such as physical activity, air pollution, diet, and sex. The establishment of large consortia and population-based cohorts, in combination with new computational tools and mouse genetics platforms, can potentially overcome some of the limitations that have hindered human GxE interaction studies and reveal additional association signals for CVD-related traits. The identification of novel GxE interactions is likely to provide a better understanding of the pathogenesis and genetic liability of CVD, with significant implications for healthy lifestyles and therapeutic strategies.

Impact of obesity on outcomes after abdominal gunshot injury.

BACKGROUND: The impact of obesity, on outcomes after a gunshot wound, remains unclear. We hypothesized that patients with obesity have a higher burden of intraabdominal injuries after gunshot injury when compared with the nonobese population. METHODS: The Trauma Quality Improvement Program database (2013-2017) was queried for all patients age ≥16 with abdominal gunshot injuries. Patients who died in the emergency department (ED), arrived without signs of life, had Abbreviated Injury Scale score ≥ 3 in any other region, or transferred from an outside hospital were excluded. The patient with obesity was defined by a body mass index ≥ 30. Demographics, injury data, and outcomes were abstracted and analyzed. Patients with obesity were compared to those with a body mass index < 30. Multivariate logistical regression was used to compare mortality between groups. RESULTS: Of 34,138 patients with gunshot injuries, there were 2,616 (7.7%) with isolated abdominal injuries. Median age is 29 years (22-39 years), 86.7% men. Eight hundred twenty-seven (31.6%) were obese. The obese group was significantly older (32 [25-42] vs. 27 [22-37]; p < 0.001) with a higher incidence of hypertension (16.8% vs. 6.3%, p < 0.001) and diabetes mellitus (7.1% vs. 2.3%, p < 0.001). There was no difference in presenting vital signs, abdominal Abbreviated Injury Scale or Injury Severity Score between groups. The rate of superficial injuries and intraabdominal organ injuries were comparable between groups. Patients with obesity had significantly higher mortality (6.5% vs. 4.2%, p = 0.010), hospital length of stay (9 [7-16] vs. 9[6-14], p < 0.001), ventilator days (3 [2-5] vs. 3 [2-4], p = 0.015), and hospital-acquired pneumonia (3.5% vs. 1.7%, p = 0.005). On multivariate analysis, in addition to older age (odds ratio [OR], 1.050; p < 0.001), ED hypotension (OR, 3.192; p < 0.001), and ED tachycardia (OR, 3.714; p < 0.001), obesity was significantly associated with mortality (OR, 1.636; p = 0.021). CONCLUSION: Patients with obesity are at a high risk of mortality after abdominal gunshot injury. Further prospective evaluation is warranted. LEVEL OF EVIDENCE: Prognostic study, Level III.

When Is It Safe to Start Pharmacologic Venous Thromboembolism Prophylaxis After Pelvic Fractures? A Prospective Study From a Level I Trauma Center.

BACKGROUND: The ideal time for pharmacologic venous thromboembolism (VTE) prophylaxis initiation after pelvic fracture is controversial. This prospective study evaluated the safety and efficacy of early VTE prophylaxis after blunt pelvic trauma. METHODS: Patients presenting to our American College of Surgeons-verified level I trauma center (between December 1, 2016 and November 30, 2017) with blunt pelvic fracture were prospectively screened. Exclusion criteria were emergency department death, immediate operative intervention, transfers, home anticoagulation, pregnancy, and patients receiving no pharmacologic VTE prophylaxis during hospitalization. Patients were dichotomized into study groups based on VTE prophylaxis initiation time ≤48 h (early prophylaxis [EP]) versus >48 h (late prophylaxis [LP]) after emergency department arrival. Demographics, injury data, clinical data, VTE prophylaxis agent and initiation time, and outcomes were compared. RESULTS: After exclusions, 146 patients were identified: 74 (51%) patients in EP group and 72 (49%) patients in LP group. Pelvic fracture severity was comparable between groups (Abbreviated Injury Scale extremity score 2 [2-3] versus 2 [2-3]; P = 0.610). On univariate analysis, deep vein thrombosis rates were higher after LP (n = 5, 7% versus 0, 0%; P = 0.027). Pulmonary embolism rates were similar (n = 2, 3% versus n = 3, 4%; P = 1.000). No patient required delayed intervention for bleeding, and postprophylaxis blood transfusion was comparable between groups (P > 0.05). On multivariate analysis, timing of pharmacologic VTE prophylaxis initiation was not associated with VTE development (odds ratio, 0.647; P = 0.999). Pelvic angioembolization was independently associated with VTE (odds ratio, 1.296; P = 0.044). CONCLUSIONS: Early initiation of pharmacologic VTE prophylaxis after blunt pelvic fracture is safe. Although EP initiation did not reduce the rate of VTE, these data identify angioembolization as an independent risk factor for VTE. Patients with blunt pelvic fracture who undergo angioembolization may therefore represent a high-risk population who may especially benefit from EP.

Complications Following Brachial Arterial Catheterization in the Surgical Intensive Care Unit.

Clinically, complication rates of brachial arterial catheterization appear to far exceed those of the radial or common femoral arteries. The study objective was to define the complication rate after brachial arterial line insertion. All patients undergoing arterial line placement to the brachial artery in the surgical intensive care units (SICUs) at our institution were retrospectively identified and included in the study (January 2016-December 2018). Demographics, complications (distal ischemia, thrombosis/dissection, brachial sheath hematoma, catheter-related sepsis, and inadvertent dislodgement), and outcomes were collected and analyzed. Over the study period, 53 patients underwent brachial arterial catheterization. Common admitting services were cardiothoracic surgery (n = 31, 58%), transplant surgery (n = 7, 13%), and neurosurgery (n = 4, 7%). The mean age was 55 ± 17 58 (24-84) years, and 58% (n = 31) were male. The hospital length of stay (LOS) was 37 ± 35 23 (1-132) days, and ICU LOS was 30 ± 27 20 (1-127) days. Mortality was 57% (n = 30). Complications of brachial arterial line placement occurred in 21 patients (40%). In summary, brachial arterial catheters were associated with high mortality and prolonged ICU length of stay. This likely reflects the critically ill nature of patients in whom conventional-site arterial line placement is not possible. Complications following brachial arterial catheterization were unacceptably high. On this basis, we recommend that the brachial artery be avoided whenever possible for arterial line placement in the SICU.

Transfusion-Related Hypocalcemia After Trauma.

BACKGROUND: Hypocalcemia is cited as a complication of massive transfusion. However, this is not well studied as a primary outcome in trauma patients. Our primary outcome was to determine if transfusion of packed red blood cells (pRBC) was an independent predictor of severe hypocalcemia (ionized calcium ≤ 3.6 mg/dL). METHODS: Retrospective, single-center study (01/2004-12/2014) including all trauma patients ≥ 18 yo presenting to the ED with an ionized calcium (iCa) level drawn. Variables extracted included demographics, interventions, outcomes, and iCa. Regression models identified independent risk factors for severe hypocalcemia (SH). RESULTS: Seven thousand four hundred and thirty-one included subjects, 716 (9.8%) developed SH within 48 h of admission. Median age: 39 (Range: 18-102), systolic blood pressure: 131 (IQR: 114-150), median Glasgow Coma Scale (GCS): 15 (IQR: 10-15), Injury Severity Score (ISS): 14 (IQR: 9-24). SH patients were more likely to have depressed GCS (13 vs 15, p < 0.0001), hypotension (23.2% vs 5.1%, p < 0.0001) and tachycardia (57.0% vs 41.9%, p < 0.0001) compared to non-SH patients. They also had higher emergency operative rate (71.8% vs 29%, p < 0.0001) and higher blood administration prior to minimum iCa [pRBC: (8 vs 0, p < 0.0001), FFP: (4 vs 0, p < 0.0001), platelet: (1 vs 0, p < 0.0001)]. Multivariable analysis revealed penetrating mechanism (AOR: 1.706), increased ISS (AOR: 1.029), and higher pRBC (AOR: 1.343) or FFP administered (AOR: 1.097) were independent predictors of SH. SH was an independent predictor of mortality (AOR: 2.658). Regression analysis identified a significantly higher risk of SH at pRBC + FFP administration of 4 units (AOR: 18.706, AUC:. 897 (0.884-0.909). CONCLUSION: Transfusion of pRBC is an independent predictor of SH and is associated with increased mortality. The predicted probability of SH increases as pRBC + FFP administration increases.

Adjunctive use of hepatic angioembolization following hemorrhage control laparotomy.

BACKGROUND: Severe liver injuries pose a challenge to trauma surgeons. While the use of hepatic angioembolization (HAE) has been evaluated as a component of the nonoperative management of liver injury, little is known about the efficacy of postoperative HAE in patients who require hemorrhage control laparotomy (HCL) for liver injury. The purpose of this study is to evaluate the impact of HAE following HCL on patient survival. METHODS: This is a retrospective cohort study using the American College of Surgeons Trauma Quality Improvement Program database from January 2013 to December 2014. In propensity score matched (2:1) patients who underwent HCL-only or HCL + HAE, the impact of adjunctive use of HAE on patient survival was examined with the Cox proportional hazards regression analysis adjusting for transfusion requirement within 4 hours. We also performed a subgroup analysis in patients without severe traumatic brain injury (Abbreviated Injury Scale head ≤3). RESULTS: A total of 1,675 patients met our inclusion criteria. Of those, 75 (4.5%) patients underwent HAE after HCL (median hours to HAE, 5 hours after admission). In 225 propensity score-matched patients, the use of HAE following HCL was significantly associated with improved 24-hour mortality, but not in-hospital mortality. In the subgroup of patients without severe traumatic brain injury (n = 189), we observed significant survival benefits (24-hour and in-hospital mortality) associated with the adjunctive use of HAE. CONCLUSION: The results of our study suggest that the adjunctive use of HAE might improve survival of patients who require HCL for liver injury. Further prospective study to determine the indication for postoperative HAE is still warranted. LEVEL OF EVIDENCE: Therapeutic study, level III.

When is It Safe to Start VTE Prophylaxis After Blunt Solid Organ Injury? A Prospective Study from a Level I Trauma Center.

BACKGROUND: The optimal timing of VTE prophylaxis initiation after blunt solid organ injury is controversial. Retrospective studies suggest initiation ≤48 h is safe. This prospective study examined the safety and efficacy of early VTE prophylaxis initiation after nonoperative blunt solid organ injury. METHODS: All patients >15 years of age presenting after blunt trauma (12/01/16-11/30/17) were prospectively screened. Patients were included if solid organ injury (liver, spleen, kidney) was diagnosed on admission CT scan and nonoperative management was planned. ED deaths, transfers, patients with pre-existing bleeding disorders or home antiplatelet/anticoagulant medications, and those who did not receive VTE prophylaxis were excluded. Demographics, injury/clinical data, type/timing of VTE prophylaxis initiation, and outcomes were collected. Patients were dichotomized into study groups based on VTE prophylaxis initiation time: Early (≤48 h) vs Late (>48 h after admission). Prophylaxis initiation was at the discretion of the attending trauma surgeon. The primary study outcome was VTE event rate. Secondary outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, need for and volume of post-prophylaxis blood transfusion, need for delayed (post-prophylaxis) interventional radiology (IR) or operative intervention, failure of nonoperative management, and mortality. Outcomes were compared with univariate analysis. Multivariate analysis with logistic regression determined independent predictors of late VTE prophylaxis initiation. RESULTS: After exclusions, 118 patients were identified. Median ISS was 22 [IQR 14-26]. Median AAST grade of injury was 2 [IQR 2-3] for liver, 2 [IQR 1-3] for spleen, and 3 [IQR 2-3] for kidney. Compared to late prophylaxis patients (n = 57, 48%), early prophylaxis patients (n = 61, 52%) had significantly fewer DVTs (n = 0, 0% vs n = 5, 9%, p = 0.024) but similar rates of PE (n = 2, 3% vs n = 3, 5%, p = 0.672). TBI was the only significant risk factor for late prophylaxis (OR 0.22, p = 0.015). No patient in either group required delayed intervention (operative or IR) for bleeding. There was no difference in volume of post-prophylaxis blood transfusion. CONCLUSIONS: In this prospective study of patients with nonoperative blunt solid organ injuries, early (≤48 h) initiation of VTE prophylaxis resulted in a lower incidence of DVTs without an associated increase in bleeding or need for intervention. Early initiation of VTE prophylaxis is likely to be safe and beneficial for patients with blunt solid organ injury.

Cannabis Use Is Associated with Increased Mechanical Ventilation and Polysubstance Use in Trauma Patients.

Recent policy changes in California regarding cannabis use underscore the need to study outcomes and prevalence of this drug in trauma. Our study aims to study the prevalence of cannabis use and associations with injury types and outcomes in Los Angeles County trauma patients. Data were reviewed from 21,276 adult patients from a Los Angeles countywide database spanning five years (2012-2016), who underwent urine toxicology testing in the ED after sustaining a traumatic injury. The percentage of trauma patients using marijuana increased from 36 to 43 per cent over the five-year period. On univariate analysis, cannabis-positive patients were significantly younger and more likely male, with lower median systolic blood pressure and heart rate on arrival in the ED. A higher proportion of cannabis users had penetrating trauma, and 48 per cent of cannabis users also tested positive for amphetamines, cocaine, opioids, or Phencyclidine. On multivariate analysis, cannabis was associated with an increase in need for mechanical ventilation after adjusting for age, admission Glasgow Coma Score, gender, polysubstance use, blunt or penetrating mechanism, and Injury Severity Score, and was not associated with increases in mortality or ICU length of stay.

Peak creatinine kinase level is a key adjunct in the evaluation of critically ill trauma patients.

BACKGROUND: Elevated creatinine kinase (CK) can indicate rhabdomyolysis, a risk factor for acute kidney injury (AKI). We investigated risk factors and clinical significance of peak CK levels. METHODS: Retrospective analysis, adult trauma patients. Logistic regression was used to identify risk factors for elevated CK and AKI. RESULTS: 3240 trauma patients were analyzed; median time to peak CK was 17 h and 347 patients had peak CK > 5000. On multivariable analysis, younger males with severe injury were more likely to have peak CK > 5000 and peak CK > 5000 was an independent risk factor for AKI (AOR 3.79). Although peak CK levels were significantly lower in older patients (1,637U/L vs 2,604U/L), older patients were more likely to develop AKI at lower CK levels. CONCLUSIONS: CK levels commonly peak within 1-2 days after admission. Despite lower peak CK levels, older patients are more likely to develop AKI. These data may support more rigorous CK monitoring and lower intervention threshold in older patients.

Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo.

Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. The treatment of the Zucker obese rats with rosiglitazone also reversed the high circulating levels of non-esterified fatty acids, which have been shown to be correlated with increased IRS1 serine phosphorylation in other animal models. Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone.