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Purpose: Research on rib fracture management has exponentially increased. Predicting fracture patterns based on the mechanism of injury (MOI) and other possible correlations may improve resource allocation and injury prevention strategies. The Chest Injury International Database (CIID) is the largest prospective repository of the operative and nonoperative management of patients with severe chest wall trauma. The purpose of this study was to determine whether the MOI is associated with the resulting rib fracture patterns. We hypothesized that specific MOIs would be associated with distinct rib fracture patterns., Methods: The CIID was queried to analyze fracture patterns based on the MOI. Patients were stratified by MOI: falls, motor vehicle collisions (MVCs), motorcycle collisions (MCCs), automobile-pedestrian collisions, and bicycle collisions. Fracture locations, associated injuries, and patient-specific variables were recorded. Heat maps were created to display the fracture incidence by rib location., Results: The study cohort consisted of 1,121 patients with a median RibScore of 2 (range, 0-3) and 9,353 fractures. The average age was 57±20 years, and 64% of patients were male. By MOI, the number of patients and fractures were as follows: falls (474 patients, 3,360 fractures), MVCs (353 patients, 3,268 fractures), MCCs (165 patients, 1,505 fractures), automobile-pedestrian collisions (70 patients, 713 fractures), and bicycle collisions (59 patients, 507 fractures). The most commonly injured rib was the sixth rib, and the most common fracture location was lateral. Statistically significant differences in the location and patterns of fractures were identified comparing each MOI, except for MCCs versus bicycle collisions., Conclusions: Different mechanisms of injury result in distinct rib fracture patterns. These different patterns should be considered in the workup and management of patients with thoracic injuries. Given these significant differences, future studies should account for both fracture location and the MOI to better define what populations benefit from surgical versus nonoperative management., Competing Interests: Conflicts of interest Evert A. Eriksson is an educational speaker for DePuy Synthes. Andrew R. Doben received royalties for an unrelated product from Zimmer Biomet and is an educational consultant for KLS Martin. The authors have no other conflicts of interest to declare., (© 2024 The Korean Society of Traumatology.)

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions., (© 2023. The Author(s).)

Background: New Chest Wall Injury and Reconstructive Centers (CWIRC) are emerging; this study aims to investigate the potential benefits of implementing a CWIRC at a single institution. We hypothesized that patients treated at CWIRC will have improved outcomes., Methods: We instituted a CWIRC in 2019 at our American College of Surgeons (ACS) Level One Trauma Center. We retrospectively compared trauma patients with rib fractures who presented to our center 18 months before (PRE-C) and 18 months after CWIRC implementation (POST-C). Outcomes measured included mortality, length of stay (LOS), intensive care unit (ICU-LOS), readmission rates, and unplanned ICU admission., Results: There were 192 PRE-C patients, compared to 388 POST-C. The mortality in PRE-C was not significantly different compared to the POST-C group (11.46% vs 8.8%, p=0.308). There were also no differences in LOS, ICU-LOS, readmission, and unplanned ICU admission. ICU utilization was dramatically different: PRE-C 17.8% were admitted to ICU compared to 35.6% POST-C (p<0.0001)., Conclusions: The number of patients admitted with rib fractures to our center nearly doubled after CWIRC establishment. Early diagnosis and triage led to significantly more admissions to higher levels of care. There are trends toward improved outcomes using practice management protocols, albeit with higher ICU utilization. Establishment of a CWIRC should be considered for level 1 ACS trauma centers and as utilization of established CWIRC protocols are increased, patients will have improved outcomes., Level of Evidence: IV STUDY TYPE: Retrospective chart review., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction Trauma patients frequently return to an emergency department (ED) soon after discharge; often for non-urgent reasons. Social factors contribute to higher ED usage. At present, there is no standardized system for reporting of ED visits and readmissions among trauma care. We hypothesized that victims of violent crime suffer from many early post-discharge adverse events that has not been captured by current methods. Methods We prospectively consented and enrolled injured patients from January 1st, 2019 to December 31st, 2019. We documented 30-day post-discharge events using post-discharge phone calls and detailed chart abstraction. Patients were categorized as victims of violence (VV) or unintentional traumatic injury (UT). Results During the study period, 444 patients were enrolled. Fifty-one (11.5%) were victims of violence and 393 (88.5%) experienced unintentional injuries. The VV patients were younger (40.10 vs 60.36; p<0.0001), and more predominantly male (92.16% vs 57.51%; p<0.0001). Total injury severity score (ISS), critical care length of stay (LOS), and total LOS were similar. VV patients were more likely discharged home (70.59% vs 55.47%; p=0.0403). They were significantly more likely to return to an emergency department (47.06% vs 23.16%; p<0.0005) and had more total number of ED visits per patient. Readmission rates, however, were not different (21.57% vs 16.28%; p=NS). The VV patients more frequently were underinsured (72.5%, vs 20.6%, p<0.005). Discussion Victims of violence presented to the ED significantly more often, despite similar injury scores, LOS, and being of younger age. Of these patients, only 26.2% of ED presentations resulted in readmission, suggesting the majority of patient complaints may have been able to be managed in an office-based setting. VV had significantly more underinsured or subsidized patients. Victims of violence are vulnerable and may benefit from more resources provided in the early post-discharge period., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Gontarz et al.)

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

[reaction: see text] A novel and efficient synthesis of isothiazolidinone protein tyrosine phosphatase mimetics is presented. A practical, regiospecific microwave-assisted addition of bisulfite to activated olefins, including unprecedented reactions with styrene derivatives, is highlighted.

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.