Initiation, dropout, and outcome from evidence-based psychotherapies in a VA PTSD outpatient clinic.

Trauma-focused, evidence-based psychotherapies (TF-EBPs) for posttraumatic stress disorder (PTSD) have been widely promoted in the Veterans Health Administration to provide access to state-of-the-art treatments, but dropout rates may affect the impact of TF-EBPs. The current study summarizes findings from a program evaluation of 67 veterans assigned to trauma-focused treatment in a Veterans Affairs outpatient PTSD clinic. Outcomes of interest include attendance rates, dropout rates and patterns, treatment paths, changes in self-reported symptoms, and clinician ratings. Nine veterans (13.4%) did not attend a first session and 15 (22.4%) dropped out before session 4. Twenty-three (33.8%) received either a modified version of the TF-EBP or switched to a different treatment. Only 11 (16.4%) completed the assigned TF-EBP, but 10 of those 11 (90.9%) were rated by their therapist as improved. These results align with previous research documenting high dropout rates from PTSD treatment in veterans and substantial improvements for those who complete TF-EBPs. Future study of methods to enhance retention in TF-EBP treatments is needed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening.

Inhibition of the Chk1 kinase by small molecules is of great therapeutic interest for oncology and in understanding the cellular regulation of the G2/M checkpoint. We report how computational docking of a large electronic catalogue of compounds to an X-ray structure of the Chk1 ATP-binding site allowed prioritisation of a small subset of these compounds for assay. This led to the discovery of 10 novel Chk1 inhibitors, distributed among nine new and clearly different chemical scaffolds. Several of these scaffolds have promising lead-like properties. All these ligands act by competitive binding to the targeted ATP site. The crystal structures of four of these compounds bound to this site are presented, and reasonable modelled docking modes are suggested for the 5 other scaffolds. This structural context is used to assess the potential of these scaffolds for further medicinal chemistry efforts, suggesting that several of them could be elaborated to make additional interactions with the buried part of the ATP site. Some unusual interactions with the conserved kinase backbone motif are pointed out. The ligand-binding modes are also used to discuss their medicinal chemistry potential with respect to undesirable chemical functionalities, whether these functionalities bind directly to the protein or not. Overall, this work illustrates how virtual screening can identify a diverse set of ligands which bind to the targeted site. The structural models for these ligands in the Chk1 ATP-binding site will facilitate further medicinal chemistry efforts targeting this kinase.

The whole truth: comparative analysis of diaphragmatic hernia repair using 4-ply vs 8-ply small intestinal submucosa in a growing animal model.

BACKGROUND: Diaphragmatic reconstruction remains a challenging problem. There is limited information concerning the use of small intestinal submucosa (SIS) in congenital diaphragmatic hernia repair. A canine model was used to evaluate the use of a SIS patch in diaphragmatic reconstruction. METHODS: Eleven beagle puppies (1.6-4.2 kg, 8 weeks old) underwent left subcostal laparotomy, central left hemidiaphragm excision (2 x 7 cm, 50% loss), and reconstruction with a 4-ply group I (n = 5) or 8-ply group II (n = 6) SIS patch. Chest radiographs were taken at time of operation and 3 and 6 months postoperatively. Animals were killed at 6 months. Adhesion formation (both pleural and abdominal), gross visual evaluation of the patch, and histology were compared. RESULTS: In group I (4-ply), 1 animal died at 3 months from patch deterioration accompanied by stomach herniation that resulted in respiratory failure. In the 4 remaining animals, chest radiographs showed no evidence of herniation or eventration. On physical examination, there was no evidence of chest wall deformity. During gross surgical examination, the 4-ply patches showed thinning, multiple defects, and liver herniation in 3 animals. In 1 pup, the patch was thickened, intact, well incorporated at the repair site, and adherent to the liver and spleen. In group II (8-ply), 1 animal died of cardiopulmonary failure in the early postoperative period. In the other 5 animals, chest radiographs showed evidence of eventration in 1. On gross examination the patch adhered to the liver in all 5 surviving animals. In 4, the patches were thickened, viable, but had some shrinkage. One patch pulled away from the native diaphragm laterally; however, no visceral herniation was present. In the 1 animal with eventration, there was no evidence of a patch. Adhesion scores (AS) were graded and determined by the sum of extent (0-4), type (0-4), and tenacity (0-3). Average abdominal AS in group I was 5.6 +/- 0.8 vs 10.2 +/- 0.2 (P = .079) for group II. Average lung AS was 0.6 +/- 0.6 in group I vs 3.8 +/- 1.1 (P = .0476) for group II. Histological examination showed group II patches had greater collagen deposition with central calcification and mild inflammation within the residual graft, whereas group I patches were much thinner and were composed of granulation tissue without evidence of residual graft. CONCLUSIONS: These data indicate that 8-ply SIS repair of diaphragmatic defects was superior (80%; 4/5 to 4-ply, 20%; 1/5, success). Organ adherence appears to be necessary for neovascularization of the SIS composite. Eight-ply grafts appear to be more durable and persist for a longer period, which may improve neovascularization. Long-term follow-up to evaluate remodeling characteristics of the patch material is required.

Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification.

Inhibition of the Chk1 kinase by small molecules binding to its active site is a strategy of great therapeutic interest for oncology. We report how computational modelling predicted the binding mode of ligands of special interest to the Chk1 ATP site, for representatives of an indazole series and debromohymenialdisine. These binding modes were subsequently confirmed by X-ray crystallography. The binding mode of a potent indazole derivative involves non-conventional C-H...O and N-H...pi-aromatic interactions with the protein. These interactions are formed in a buried pocket at the periphery of the ATP-binding site, the importance of which has previously been overlooked for ligand design against Chk1. It is demonstrated that filling this pocket can confer ligands with dramatically enhanced affinity for Chk1. Structural arguments in conjunction with assay data explain why targeting this pocket is also advantageous for selective binding to Chk1. Structural overlays of known inhibitors complexed with Chk1 show that only the indazole series utilizes the pocket of interest. Therefore, the analysis presented here should prove helpful in guiding future structure-based ligand design efforts against Chk1.

Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity.

We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.