Injury Characteristics and Outcomes of Patients With Inflammatory Bowel Disease After Trauma: A Propensity Score Matched Analysis.

BACKGROUND: The clinical course of patients with inflammatory bowel disease (IBD) after trauma is largely unknown. We sought to compare the clinical course of patients with IBD to those without. METHODS: We conducted a retrospective case-control study of adult patients admitted to a level-1 trauma center from January 1, 2008, through October 1, 2015. Seventy-five patients with IBD were identified. Cases were matched to controls by age, sex, injury severity, and mechanism using 4:1 propensity score-matching analysis. Injury characteristics, clinical course, and infectious and noninfectious complications were compared using bivariate and multivariate analysis. RESULTS: Participants had a mean age of 56 years and mean injury severity score of 15. Of the 75 cases, 44% had ulcerative colitis, 44% had Crohn's disease, and 12% had undetermined type. More cases were on an immunosuppressant (19% vs 2%, P < 0.01) or steroids (8% vs 2%, P = 0.02) on admission compared with controls. More cases had prior abdominal surgery (P = 0.01). Cases had fewer brain injuries (P = 0.02) and higher admission Glasgow Coma Scale (P < 0.01) but required more neurosurgical intervention (P = 0.03). Cases required more orthopedic surgeries (P < 0.01) and more pain management consultations (P = 0.04). In multivariable analysis, IBD was associated with increased odds of operative intervention, pain management consultation, venous thromboembolism, and longer hospital stay (P < 0.05). Patients on immunosuppressants had increased odds of requiring surgery (P = 0.04), particularly orthopedic surgery (P < 0.01). CONCLUSIONS: Baseline factors associated with inflammatory bowel disease may place patients at higher risk for surgery and complications after trauma.

Task Shifting: The Use of Laypersons for Acquisition of Vital Signs Data for Clinical Decision Making in the Emergency Room Following Traumatic Injury.

IMPORTANCE: In resource-limited settings, identification of successful and sustainable task-shifting interventions is important for improving care. OBJECTIVE: To determine whether the training of lay people to take vital signs as trauma clerks is an effective and sustainable method to increase availability of vital signs in the initial evaluation of trauma patients. DESIGN: We conducted a quasi-experimental study of patients presenting with traumatic injury pre- and post-intervention. SETTING: The study was conducted at Kamuzu Central Hospital, a tertiary care referral hospital, in Lilongwe, Malawi. PARTICIPANTS: All adult (age ≥ 18 years) trauma patients presenting to emergency department over a six-month period from January to June prior to intervention (2011), immediately post-intervention (2012), 1 year post-intervention (2013) and 2 years post-intervention (2014). INTERVENTION: Lay people were trained to take and record vital signs. MAIN OUTCOMES AND MEASURES: The number of patients with recorded vital signs pre- and post-intervention and sustainability of the intervention as determined by time-series analysis. RESULTS: Availability of vital signs on initial evaluation of trauma patients increased significantly post-intervention. The percentage of patients with at least one vital sign recorded increased from 23.5 to 92.1%, and the percentage of patients with all vital signs recorded increased from 4.1 to 91.4%. Availability of Glasgow Coma Scale also increased from 40.3 to 88.6%. Increased documentation of vital signs continued at 1 year and 2 years post-intervention. However, the percentage of documented vital signs did decrease slightly after the US-trained medical student and surgeon who trained the trauma clerks were no longer available in country, except for Glasgow Coma Scale. Patients who died during emergency department evaluation were significantly less likely to have vital signs recorded. CONCLUSIONS AND RELEVANCE: The training of lay people to collect vital signs and Glasgow Coma Scale is an effective and sustainable method of task shifting in a resource-limited setting.

Injury Characteristics and Outcomes in Elderly Trauma Patients in Sub-Saharan Africa.

BACKGROUND: Traumatic injury in the elderly is an emerging global problem with an associated increase in morbidity and mortality. This study sought to describe the epidemiology of elderly injury and outcomes in sub-Saharan Africa. METHODS: We conducted a retrospective analysis of adult patients (≥ 18 years) with traumatic injuries presenting to the Kamuzu Central Hospital (KCH) in Lilongwe, Malawi, over 5 years (2009-2013). Elderly patients were defined as adults aged ≥65 years and compared to adults aged 18-44 and 45-64 years. We used propensity score matching and logistic regression to compare the odds of mortality between age groups using the youngest age group as the reference. RESULTS: 42,816 Adult patients with traumatic injuries presented to KCH during the study period. 1253 patients (2.9 %) were aged ≥65 years with a male preponderance (77.4 %). Injuries occurred more often at home as age increased (25.3, 29.5, 41.1 %, p < 0.001) and falls were more common (14.1, 23.8, 36.3 %, p < 0.001) for elderly patients. Elderly age was associated with a higher proportion of hospital admissions (10.6, 21.3, 35.2 %, p < 0.001). Upon propensity score matching and logistic regression analysis, the odds ratio of mortality for patients aged ≥65 was 3.15 (95 % CI 1.45, 6.82, p = 0.0037) compared to the youngest age group (18-44 years). CONCLUSIONS: Elderly trauma in a resource-poor area in sub-Saharan Africa is associated with a significant increase in hospital admissions and mortality. Significant improvements in trauma systems, pre-hospital care, and hospital capacity for older, critically ill patients are imperative.

The utility of the Kampala trauma score as a triage tool in a sub-Saharan African trauma cohort.

BACKGROUND: Trauma scoring systems have been developed to assess injury severity and may have triage potential. We sought to evaluate the ability of the Kampala trauma score (KTS) to assess injury severity and its potential as an outcome predictive tool in Malawi. METHODS: This is a prospective cohort study of trauma patients presenting to Kamuzu Central Hospital in 2012. We recorded admission KTS and Revised trauma score (RTS), emergency department disposition, and hospital length of stay (LOS) and survival. Logistic regression and ROC curve analyses were used to compare the KTS to the widely accepted RTS. RESULTS: 15,617 patients presented with trauma. 2,884 (18 %) were admitted, of which 2,509 (95 %) survived. The mean admission KTS was 14.5 ± 0.6, and RTS was 11.9 ± 0.3. For KTS and RTS, the odds of admission with each increment increase in score was 0.44 and 0.3, respectively. Similarly, odds of mortality is 0.48 and 0.36. Neither KTS (p = 0.96, ROC area 0.5) nor RTS (p = 0.25, ROC area 0.5) correlated significantly with hospital LOS. KTS and RTS performed equally well as predictors of mortality, but KTS was a better predictor of need for admission (KTS ROC area 0.62, RTS ROC area 0.55, p < 0.001). CONCLUSIONS: Both the KTS and RTS were significantly associated with need for admission and final outcome on logistic regression analysis; however, they may not be strong enough predictors to merit their use as a screening tool in our setting.

Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

P2Y1 receptor antagonists as novel antithrombotic agents.

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.

Discovery of highly potent and selective benzyloxybenzyl-based peroxisome proliferator-activator receptor (PPAR) delta agonists.

A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.

Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor delta agonists.

Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.

Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties.

A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.

Interaction with the S1 beta-pocket of urokinase: 8-heterocycle substituted and 6,8-disubstituted 2-naphthamidine urokinase inhibitors.

Several 8-substituted 2-naphthamidine-based inhibitors of the serine protease urokinase plasminogen activator (uPA) are described. Direct attachment of five-membered saturated or unsaturated rings improved inhibitor performance; substitution with sulfones further improved binding profiles. Combination of these substituents or of previously described NH-linked heteroaromatic rings with 6-phenyl amide substituents provided further enhancements to potency and selectivity.

Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution.

The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.