Trauma surgeons experience compassion fatigue: A major metropolitan area survey.

INTRODUCTION: Compassion fatigue (CF), the physical, emotional, and psychological impact of helping others, is composed of three domains: compassion satisfaction (CS), secondary traumatic stress (STS), and burnout (BO). Trauma surgeons (TSs) experience work-related stress resulting in high rates of CF, which can manifest as physical and psychological disorders. We hypothesized that TSs experience CF and there are potentially modifiable systemic factors to mitigate its symptoms. METHODS: All TSs in a major metropolitan area were eligible. Personal and professional demographic information was obtained. Each participant completed six validated surveys: (1) Professional Quality of Life scale, (2) Perceived Stress Scale, (3) Multidimensional Scale of Perceived Social Support, (4) Adverse Childhood Events Questionnaire, (5) Brief Coping Inventory, and (6) Toronto Empathy Questionnaire. Compassion fatigue subscale risk scores (low, <23; moderate, 23-41; high, >41) were recorded. Linear regression analysis assessed the demographic and environmental factors association with BO, STS, and CS. Variables significant on univariate analysis were included in multivariate models to determine the independent influence on BO, STS, and CS. Significance was p ≤ 0.05. RESULTS: There were 57 TSs (response rate, 75.4% [n = 43]; White, 65% [n = 28]; male, 67% [n = 29]). Trauma surgeons experienced CF (BO, 26 [interquartile range (IQR), 21-32]; STS, 23 [IQR, 19-32]; CS, 39 [IQR, 34-45]). The Perceived Stress Scale score was significantly associated with increased BO (coefficient [coef.], 0.52; 95% confidence interval [CI], 0.28-0.77) and STS (coef., 0.44; 95% CI, 0.15-0.73), and decreased CS (coef., -0.51; 95% CI, -0.80 to -0.23) ( p < 0.01). Night shifts were associated with higher BO (coef., 1.55; 95% CI, 0.07-3.03; p = 0.05); conversely, day shifts were associated with higher STS (coef., 1.94; 95% CI, 0.32-3.56; p = 0.03). Higher Toronto Empathy Questionnaire scores were associated with greater CS (coef., 0.33; 95% CI, 0.12-0.55; p < 0.01). CONCLUSION: Trauma surgeons experience moderate BO and STS associated with modifiable system- and work-related stressors. Efforts to reduce CF should focus on addressing sources of workplace stress and promoting empathic care. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

A real-world observational study assessing relationships between excessive daytime sleepiness and patient satisfaction in obstructive sleep apnea.

OBJECTIVES/BACKGROUND: To estimate prevalence and severity of excessive daytime sleepiness among patients with obstructive sleep apnea (OSA) who were prescribed treatment; assess perception and satisfaction of OSA-related care; describe relationships between excessive daytime sleepiness, treatment adherence, and patient satisfaction. PATIENTS/METHODS: A national population-based cross-sectional sample of US adults with clinician-diagnosed OSA was surveyed in January 2021 via Evidation Health's Achievement App. Patients completed the Epworth Sleepiness Scale, rated satisfaction with healthcare provider and overall OSA care, and reported treatment adherence. Covariates affecting excessive daytime sleepiness (average weekly sleep duration, treatment adherence, sleepiness-inducing medications, age, sex, body mass index, nasal congestion, smoking status, and comorbidities) were adjusted in multivariate regression models. RESULTS: In 2289 participants (50.3 % women; 44.8 ± 11.1 years), EDS was highly prevalent (42 %), and was experienced by 36 % of patients with high positive airway pressure (PAP) therapy adherence. Each additional hour of nightly PAP use was associated with improved sleepiness (a 0.28-point lower Epworth score; p < 0.001). Excessive daytime sleepiness was associated with lower patient satisfaction with healthcare providers and overall care (OR [95 % CI] 0.62 [0.48-0.80] and 0.50 [0.39-0.64], respectively; p < 0.0001), whereas PAP adherence was associated with higher patient satisfaction (OR [95 % CI] 2.37 [1.64-3.43] and 2.91 [2.03-4.17]; p < 0.0001), after adjusting for confounders. CONCLUSIONS: In a real-world population-based study of patients with OSA, excessive daytime sleepiness was highly prevalent and associated with poor patient satisfaction ratings. Better patient-centered care among patients with OSA may require interventions aimed at addressing excessive daytime sleepiness and treatment adherence.

When public health crises collide: 5 years of pediatric firearm injury prevention opportunities.

Objectives: Prior publications on pediatric firearm-related injuries have emphasized significant social disparities. The pandemic has heightened a variety of these societal stresses. We sought to evaluate how we must now adapt our injury prevention strategies. Patients and methods: Firearm-related injuries in children 15 years old and under at five urban level 1 trauma centers between January 2016 and December 2020 were retrospectively reviewed. Age, gender, race/ethnicity, Injury Severity Score, situation, timing of injury around school/curfew, and mortality were evaluated. Medical examiner data identified additional deaths. Results: There were 615 injuries identified including 67 from the medical examiner. Overall, 80.2% were male with median age of 14 years (range 0-15; IQR 12-15). Black children comprised 77.2% of injured children while only representing 36% of local schools. Community violence (intentional interpersonal or bystander) injuries were 67.2% of the cohort; 7.8% were negligent discharges; and 2.6% suicide. Median age for intentional interpersonal injuries was 14 years (IQR 14-15) compared with 12 years (IQR 6-14, p<0.001) for negligent discharges. Far more injuries were seen in the summer after the stay-at-home order (p<0.001). Community violence and negligent discharges increased in 2020 (p=0.004 and p=0.04, respectively). Annual suicides also increased linearly (p=0.006). 5.5% of injuries were during school; 56.7% after school or during non-school days; and 34.3% were after legal curfew. Mortality rate was 21.3%. Conclusions: Pediatric firearm-related injuries have increased during the past 5 years. Prevention strategies have not been effective during this time interval. Prevention opportunities were identified specifically in the preteenage years to address interpersonal de-escalation training, safe handling/storage, and suicide mitigation. Efforts directed at those most vulnerable need to be reconsidered and examined for their utility and effectiveness. Level of evidence: Level III; epidemiological study type.

The tight rope act: A multicenter regional experience of tourniquets in acute trauma resuscitation.

BACKGROUND: As tourniquets have become more prevalent, device use has been questioned. This study sought to characterize the incidence, indication, and efficacy of tourniquet placement in acute trauma resuscitation. METHODS: Nine regional level 1 trauma centers prospectively enrolled for 12 months adult patients (18 years or older) who had a tourniquet placed. Age, sex, mechanism, tourniquet type, indication, applying personnel, location placed, level of occlusion, and degree of hemostasis were collected. Major vascular injury, imaging and operations performed, and outcomes were assessed. Analyses were performed with significance at p < 0.05. RESULTS: A total of 216 tourniquet applications were reported on 209 patients. There were significantly more male patients (183 [88%]) and penetrating injuries (186 [89%]) with gunshots being most common (127 [61%]). Commercial tourniquets were most often used (205 [95%]). Ninety-two percent were placed in the prehospital setting (by fire/paramedics, 56%; police, 33%; bystanders, 2%). The most common indications were pooling (47%) and pulsatile (32%) hemorrhage. Only 2% were for amputation. The most frequent location was high proximal extremity (70%). Four percent were placed over the wound, and 0.5% were distal to the wound. Only 61% of applications were arterial occlusive. Median application time was 30 minutes (interquartile range, 20-40 minutes). Imaging was performed in 54% of patients. Overall, 36% had a named arterial injury. Tourniquet application failed to achieve hemostasis in 22% of patients with a named vascular injury. There was no difference in hemostasis between those with and without vascular injury (p = 0.12) or between who placed the tourniquet (p = 0.07). Seventy patients (34%) required vascular operations. Thirty-four percent of patients were discharged home without admission. CONCLUSION: Discerning which injuries require tourniquets over pressure dressings remains elusive. Trained responders had high rates of superfluous and inadequate deployments. As tourniquets continue to be disseminated, emphasis should be placed on improving education, device development, and quality control. LEVEL OF EVIDENCE: Prognostic/Epidemiologic, Level III.

Treatment of Partial Thickness Burns: A Prospective, Randomized Controlled Trial Comparing Four Routinely Used Burns Dressings in an Ambulatory Care Setting.

This prospective, randomized controlled trial study compared the effects of four dressings for adult partial thickness burns, focusing on re-epithelialization time and cost effectiveness. Adults with partial thickness burns meeting inclusion criteria were randomized to either Biobrane™, Acticoat™, Mepilex® Ag, or Aquacel® Ag. Primary endpoint for analysis was >95% re-epithelialization. Incremental cost-effectiveness ratios were calculated based on dressing costs. Dominance probabilities between treatment arms were calculated from bootstrap resampling trial data. One hunderd thirty-one partial thickness burn wounds in 119 patients were randomized. Adjusting for sex, age, smoking status, burn mechanism, TBSA, and first aid adequacy, Mepilex® Ag had a reduced time to re-epithelialization compared to Biobrane™ (IRR: 1.26; 95% CI: 1.07-1.48, P < .01). Economic analysis showed that there was a 99%, 71%, and 53% probability that Mepilex® Ag dominated (cheaper and more effective) Biobrane™, Acticoat™, and Aquacel® Ag, respectively. Mepilex® Ag achieved faster re-epithelialization and better cost effectiveness. Patient satisfaction and comfort seems better with Biobrane™ although not reflected within the end outcome of the healed wound. It is the patients' (after extensive education) and clinicians' choice, level of experience, and availability of products in praxis that will guide the decision as to which the product is used individually on which patient.

Traumatic abdominal wall hernias: a single-center case series of surgical management.

BACKGROUND: Traumatic abdominal wall hernias (TAWHs) are a rare clinical entity that can be difficult to diagnose and manage. There is no consensus on management of TAWH due to its low incidence and complex concomitant injury patterns. We hereby present the largest single-center case series in the USA to characterize associated injury patterns, identify optimal strategies for hernia management, and determine outcomes. METHODS: Patients who presented with a TAWH from blunt trauma requiring operative management were retrospectively identified over a 14-year period. Demographic data, Injury Severity Score (ISS), associated injuries, type of repair, durability of repair, and complications were collected, and descriptive statistics were calculated. RESULTS: Fifteen patients were identified. The average age was 31±11 years, ISS 15±9, and body mass index 33.4±7.1 kg/m2. Mechanisms included falls (13%), motor vehicle collisions (60%), motorcycle accidents (20%), and pedestrian versus motor vehicle collisions (7%). The most commonly associated injuries included colonic injuries (53%), long bone fractures (47%), pelvic fractures (40%), and small bowel injuries (33%). Nineteen hernia repairs were performed: 6 underwent primary suture repair (32%) and 13 used mesh (68%). There were four recurrences. We could not find any significant relationship between contamination and mesh use or recurrence. There was one mortality related to sepsis. DISCUSSION: TAWHs have an associated injury pattern involving fractures and abdominopelvic visceral injuries where a tailored approach is advisable. Without hollow viscous injuries and gross contamination, these hernias can be repaired safely with mesh in the acute setting. However, in patients with gross contamination or hemodynamic instability, the risk of recurrence with primary repair must be weighed against the risk of infection and prolonged surgery with mesh repair. In those cases, a delayed reconstruction in the elective setting may be optimal.

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient's CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient's CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Anticancer drug impact on DNA - a study by neutron spectroscopy coupled with synchrotron-based FTIR and EXAFS.

Complementary structural and dynamical information on drug-DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(ii) and Pd(ii) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA's dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- and mid-infrared measurements allowed the first simultaneous detection of the drugs and their primary pharmacological target, as well as the drug-prompted changes in DNA's conformation that mediate cytotoxicity. The local environment of the absorbing Pd(ii) and Pt(ii) centers in the drugs' adducts with adenine, guanine and glutathione was attained by EXAFS.

A Traumatic Direct Inguinal Hernia from Pelvic Ring Disruption.

INTRODUCTION: Pelvic fractures usually involve a high-energy traumatic mechanism and account for approximately 3% of all blunt traumatic skeletal injuries. Additional musculoskeletal injuries are found in over 80% of unstable pelvic fractures. Traumatic abdominal wall hernias (TAWHs) are a rare entity, and traumatic inguinal hernias (TIHs) associated with open-book pelvic fractures have not been described previously. CASE PRESENTATION: We present the case of a 45-year-old male motorcyclist involved in a collision resulting in a traumatic direct inguinal hernia due to abdominal wall disruption from an open-book pelvic fracture. He underwent a combined operation with an open reduction and internal fixation (ORIF) of his pelvic fracture and an abdominal wall reconstruction with a modified Stoppa technique utilizing mesh for his hernia. DISCUSSION: This is a unique presentation of a TIH due to an open-book pelvic fracture after blunt abdominal trauma. The formation of TAWH is typically from a combination of local tangential shearing forces and a sudden rise in intraabdominal pressures damaging the muscle, fascia, and peritoneum while the skin remains intact. In patients without hollow viscous injuries and gross contamination, these hernias can be repaired safely with mesh in the acute setting simultaneously with pelvic reduction.

Increased optical pathlength through aqueous media for the infrared microanalysis of live cells.

The study of live cells using Fourier transform infrared spectroscopy (FTIR) and FTIR microspectroscopy (FT-IRMS) intrinsically yields more information about cell metabolism than comparable experiments using dried or chemically fixed samples. There are, however, a number of barriers to obtaining high-quality vibrational spectra of live cells, including correction for the significant contributions of water bands to the spectra, and the physical stresses placed upon cells by compression in short pathlength sample holders. In this study, we present a water correction method that is able to result in good-quality cell spectra from water layers of 10 and 12 µm and demonstrate that sufficient biological detail is retained to separate spectra of live cells based upon their exposure to different novel anti-cancer agents. The IR brilliance of a synchrotron radiation (SR) source overcomes the problem of the strong water absorption and provides cell spectra with good signal-to-noise ratio for further analysis. Supervised multivariate analysis (MVA) and investigation of average spectra have shown significant separation between control cells and cells treated with the DNA cross-linker PL63 on the basis of phosphate and DNA-related signatures. Meanwhile, the same control cells can be significantly distinguished from cells treated with the protein kinase inhibitor YA1 based on changes in the amide II region. Each of these separations can be linked directly to the known biochemical mode of action of each agent. Graphical abstract.

Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats.

RATIONALE: Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown. OBJECTIVES: The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529. RESULTS: Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92 mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3 mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14 days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior. CONCLUSIONS: These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.

Attenuated effects of experimenter-administered heroin in adolescent vs. adult male rats: physical withdrawal and locomotor sensitization.

OBJECTIVES: Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization. METHODS: Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 h, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 h after the last injection, and then every 24 h for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at four points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation. RESULTS: A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages. CONCLUSION: Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence.

A role for the prefrontal cortex in heroin-seeking after forced abstinence by adult male rats but not adolescents.

Adolescent drug abuse is hypothesized to increase the risk of drug addiction. Yet male rats that self-administer heroin as adolescents show attenuated drug-seeking after abstinence, compared with adults. Here we explore a role for neural activity in the medial prefrontal cortex (mPFC) in age-dependent heroin-seeking. Adolescent (35-day-old at start; adolescent-onset) and adult (86-day-old at start) male rats acquired lever-pressing maintained by heroin using a fixed ratio one reinforcement schedule (0.05 and 0.025 mg/kg per infusion). Following 12 days of forced abstinence, rats were tested for heroin-seeking over 1 h by measuring the number of lever presses on the active lever. Unbiased stereology was then used to estimate the number of Fos-ir(+) and Fos-ir(-) neurons in prelimbic and infralimbic mPFC. As before, adolescents and adults self-administered similar amounts of heroin, but subsequent heroin-seeking was attenuated in the younger rats. Similarly, the adolescent-onset group failed to show significant neural activation in the prelimbic or infralimbic mPFC during the heroin-seeking test, whereas the adult-onset heroin self-administration group showed two to six times more Fos-ir(+) neurons than their saline counterparts in both mPFC subregions. Finally, the overall number of neurons in the infralimbic cortex was greater in rats from the adolescent-onset groups than adults. The mPFC may thus have a key role in some age-dependent effects of heroin self-administration.

Selective, direct activation of high-conductance, calcium-activated potassium channels causes smooth muscle relaxation.

High-conductance calcium-activated potassium (Maxi-K) channels are present in smooth muscle where they regulate tone. Activation of Maxi-K channels causes smooth muscle hyperpolarization and shortening of action-potential duration, which would limit calcium entry through voltage-dependent calcium channels leading to relaxation. Although Maxi-K channels appear to indirectly mediate the relaxant effects of a number of agents, activators that bind directly to the channel with appropriate potency and pharmacological properties useful for proof-of-concept studies are not available. Most agents identified to date display significant polypharmacy that severely compromises interpretation of experimental data. In the present study, a high-throughput, functional, cell-based assay for identifying Maxi-K channel agonists was established and used to screen a large sample collection (>1.6 million compounds). On the basis of potency and selectivity, a family of tetrahydroquinolines was further characterized. Medicinal chemistry efforts afforded identification of compound X, from which its two enantiomers, Y and Z, were resolved. In in vitro assays, Z is more potent than Y as a channel activator. The same profile is observed in tissues where the ability of either agent to relax precontracted smooth muscles, via a potassium channel-dependent mechanism, is demonstrated. These data, taken together, suggest that direct activation of Maxi-K channels represents a mechanism to be explored for the potential treatment of a number of diseases associated with smooth muscle hyperexcitability.

Comparison of nonoperative management with renorrhaphy and nephrectomy in penetrating renal injuries.

BACKGROUND: We reviewed our experience with penetrating renal injuries to compare nonoperative management of penetrating renal injuries with renorrhaphy and nephrectomy in light of concerns for unnecessary explorations and increased nephrectomy rates. METHODS: In this retrospective study, we reviewed the records of 98 penetrating renal injuries from 2003 to 2008. Renal injuries were classified according to the American Association for the Surgery of Trauma and analyzed based on nephrectomy, renorrhaphy, and nonoperative management. Patient characteristics and outcomes measured were compared between management types. Continuous variables were summarized by means and compared using t test. Categorical variables were compared using χ² test. RESULTS: Nonoperative management was performed in 40% of renal injuries, followed by renorrhaphy (38%) and nephrectomy (22%). Of renal gunshot wounds (n = 79), 26%, 42%, and 32% required nephrectomy, renorrhaphy, and were managed nonoperatively, respectively. No renal stab wound (n = 16) resulted in a nephrectomy and 81% were managed conservatively. Renal injuries managed nonoperatively had a lower incidence of transfusion (34 vs. 95%, p < 0.001), shorter mean intensive care unit (ICU) (3.0 vs. 9.0 days, p = 0.028) and mean hospital length of stay (7.9 vs. 18.1 days, p = 0.006), and lower mortality rate (0 vs. 20%, p = 0.005) compared with nephrectomy but similar to renorrhaphy (transfusion: 34 vs. 36%, p = 0.864; mean ICU: 3.0 vs. 2.8 days, p = 0.931; mean hospital length of stay: 7.9 vs. 11.2 days, p = 0.197; mortality: 0 vs. 6%, p = 0.141). The complication rate of nonoperative management was favorable compared with operative management. CONCLUSIONS: Selective nonoperative management of penetrating renal injuries resulted in a lower mortality rate, lower incidence of blood transfusion, and shorter mean ICU and hospital stay compared with patients managed by nephrectomy but similar to renorrhaphy. Complication rates were low and similar to operative management.

Elucidation of a novel bioactivation pathway of a 3,4-unsubstituted isoxazole in human liver microsomes: formation of a glutathione adduct of a cyanoacrolein derivative after isoxazole ring opening.

Studies on the biotransformation of isoxazole rings have shown that molecules containing a C3-substituted isoxazole or a 1,2-benzisoxazole can undergo a two-electron reductive ring cleavage to form an imine. In the absence of a C3 substituent, the isoxazole ring opens via deprotonation of the C3 proton followed by N-O bond cleavage to yield an α-cyanoenol analog. We report the identification of a novel bioactivation pathway of a 3,4-unsubstituted isoxazole in human liver microsomes. After the enzyme-catalyzed cleavage of the 3,4-unsubstituted isoxazole ring of N-((2-isopropyl-7-methyl-1-oxoisoindolin-5-yl)methyl)isoxazole-5-carboxamide (P) in human liver microsomes, the formed α-cyanoenol (M1) condenses with formaldehyde to generate an α,ß-unsaturated Michael acceptor intermediate (a cyanoacrolein derivative, VII), which further reacts with the cysteinyl thiol of glutathione to yield a GSH adduct of a cyanoacrolein derivative (M3). The same adduct also is formed when M1, generated in 0.1 N NaOH aqueous solution, reacts with formaldehyde and GSH. (13)C-labeled methanol was used to confirm that methanol from the drug stock solution was oxidized by liver microsomal enzymes to formaldehyde and the carbon atom from methanol was finally incorporated in the corresponding GSH adduct. The formation of isoxazole ring-opened products (M1 and M2) in human liver microsomes is NADPH-dependent. M1 and M2 were found in human liver microsomes preincubated with 1-aminobenzotriazole (1 mM) and NADPH (5 mM) at ∼ 10% of the levels found in the samples in the absence of 1-aminobenzotriazole, suggesting that this biotransformation pathway is primarily catalyzed by cytochrome P450. The formation of M3 also was inhibited by 1-aminobenzotriazole at a similar level.

Synthesis and biological activity of 2H-quinolizin-2-one based p38alpha MAP kinase inhibitors.

The development and synthesis of potent p38alpha MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed.

Management options of colonoscopic splenic injury.

Injury to the spleen during routine colonoscopy is an extremely rare injury. Diagnosis and management of the injury has evolved with technological advances and experience gained in the management of splenic injuries sustained in trauma. Of the 37 reported cases of colonoscopic splenic injury, 12 had a history of prior surgery or a disease process suggesting the presence of adhesions. Only 6 had noted difficulty during the procedure, and 31 patients experienced pain, shock, or hemoglobin drop as the indication of splenic injury. Since 1989, 21/24 (87.5%) patients have been diagnosed initially using computed tomography or ultrasonography. Overall, only 27.8% have retained their spleens. None have experienced as long a delay as our patient, nor have any had an attempt at percutaneous control of the injury. This report presents an unusual case of a rare complication of colonoscopy and the unsuccessful use of one nonoperative technique, and reviews the experience reported in the world literature, including current day management options.

p38 MAP kinase inhibitors: metabolically stabilized piperidine-substituted quinolinones and naphthyridinones.

Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.

p38 Inhibitors: piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones.

We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.