Feasibility and Acceptability of Group-Facilitated Prolonged Exposure Therapy for PTSD in VA Residential Rehabilitation Treatment Programs.

Prolonged Exposure therapy (PE) is a first-line treatment for posttraumatic stress disorder (PTSD); however, few VA patients receive this treatment. One of the barriers to PE receipt is that it is only available in an individual (one-on-one) format, whereas many VA mental health clinics provide the majority of their psychotherapy services in group format. In particular, PTSD residential rehabilitation treatment programs (RRTPs) offer most programming in group format. Consequently, strategies are needed to improve the scalability of PE by adapting it to fit the delivery setting. The current study was designed to pilot test a group-facilitated format of PE in RRTPs. Thirty-nine Veterans who were engaged in care in the PTSD RRTP at a Midwestern VA were recruited to participate in a Group-facilitated PE protocol. Participants engaged in twelve 90-minute sessions of Group PE over the course of 6 weeks, plus six 60-minute individual sessions for imaginal exposure. Group treatment followed the PE model and consisted of psychoeducation, treatment rationale, and in vivo exposure to reduce trauma-related avoidance and thereby improve PTSD symptoms. PTSD symptoms were measured via the PTSD Checklist for DSM-5 (PCL-5) and depression symptoms were measured via the Patient Health Questionnaire (PHQ-9) at baseline, endpoint (6 weeks), and at 2-month follow-up. Thirty-nine individuals initiated Group-facilitated PE and 34 completed treatment. The average number of group sessions attended was 11 out of 12. Acceptability ratings were high. Mean change (improvement) in the intent-to-treat sample at 2-month follow-up was 20.0 points on the PCL-5 (CI 18.1, 21.9; Cohen's d = 1.1) and 4.8 points on the PHQ-9 (CI 4.1, 5.5, d = .8). These results suggest that adapted evidence-based interventions for PTSD can improve treatment access and efficiency for the RRTP setting. A group-based approach has the potential to improve the scalability of PTSD treatment by reducing required resources. A fully powered trial is now needed to test the effectiveness of Group-facilitated PE in the RRTP setting.

Serological testing on the ADVIA Centaur system for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus in specimens from deceased and living individuals demonstrates equivalent resultsƚ.

INTRODUCTION: To determine the suitability of human tissues and cells for transplantation, guidelines mandate infectious disease testing of serum or plasma obtained from deceased donors, which are often collected after cessation of the heartbeat. Tests used for this purpose are required to show equivalent performance when compared to pre-mortem specimens. This study evaluated whether serology assays for HIV Ag/Ab Combo, hepatitis B virus (HBc Total; HBsAgII), and HCV on the ADVIA Centaur system, were fit for testing post-mortem sera. Performance evaluation studies included precision, specificity, and sensitivity. METHODS: Blood specimens were collected within 24 h after death from 82 deceased and 83 healthy living individuals. Studies followed standard guidelines. The 20-day precision study was performed on five levels of post-mortem specimens (non-spiked and spiked). The specificity study compared 81-83 pre-mortem and 74-82 post-mortem specimens. The sensitivity study compared 50 pre-mortem and 50 post-mortem specimens spiked with positive sera for each analyte at two levels to achieve a low (near cutoff) positive result and a second higher positive result. RESULTS: Precision, specificity, and sensitivity study results met acceptance criteria for all assays and lots; post-mortem and pre-mortem results were equivalent. CONCLUSION: Based on this study, the ADVIA Centaur CHIV, HBcT, HBsAgII, and HCV assays are acceptable for use in routine testing of deceased donor sera collected after cessation of the heartbeat.

The Association Between Service Connection and Treatment Outcome in Veterans Undergoing Residential PTSD Treatment.

The Department of Veterans Affairs has invested significant time and resources into the treatment of posttraumatic stress disorder (PTSD). Despite concerted efforts, a significant portion of patients do not respond optimally to trauma-focused treatment. One of the factors that has been hypothesized to be associated with treatment response is participation in the Veterans Benefits Administration service-connected disability process. This factor may be particularly relevant in the residential treatment setting, where most participants are engaged in the compensation seeking process. We conducted a retrospective chart review of 105 veterans who completed Cognitive Processing Therapy (CPT) in a residential rehabilitation program. ANCOVAs that adjusted for baseline PTSD severity compared symptom change between those who were and were non-compensation seeking at the time of treatment. Compensation seeking status was associated with significantly less symptom improvement over the course of CPT after adjusting for baseline PTSD severity (F(1, 102) = 4.29, p < .001, η2 = .03). Sensitivity analyses did not detect a similar effect during a prior coping skills phase of treatment. During CPT, clinically significant change was met by 66.7% of non-compensation seeking veterans (M = -15, SD = 14.56) and by 40.1% of the compensation seeking group (M = -7.1, SD = 12.24). Compensation-seeking may be associated with reduced response to trauma-focused treatment in certain settings. Future research is needed to better understand the mechanisms underlying this effect.

Residential PTSD treatment outcomes during cognitive processing therapy for veterans with and without recent histories of cannabis use.

Prior evidence has suggested that cannabis use is associated with greater posttraumatic stress disorder (PTSD) symptom severity and worse outcomes following trauma-focused treatment. However, lack of high-quality randomized studies necessitates the use of clinical data to clarify the relationship between cannabis use and PTSD treatment to help inform clinical practice. A total of 114 veterans completed cognitive processing therapy in a residential PTSD treatment program. Differences in treatment response between cannabis users and nonusers were evaluated for measures of PTSD, depression, and posttraumatic growth using analysis of covariance to control for pretreatment scores and other drug use. At baseline, cannabis users reported higher levels of PTSD symptom severity relative to nonusers but reported similar levels of depression and posttraumatic growth. Significant differences between groups in the amount of change were not observed on any of the measures from before to after treatment; however, the total sample reported significant improvements in all measures of interest. These results suggest that PTSD treatment outcomes for cannabis users may be similar to nonusers when use is stopped during treatment. Additional data are needed regarding whether outcomes remain similar at follow-up, whether cannabis users maintain abstinence after treatment, and the impact of resumed cannabis use on PTSD symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Streptococcus pyogenes pbp2x Mutation Confers Reduced Susceptibility to ß-Lactam Antibiotics.

Two near-identical clinical Streptococcus pyogenes isolates of emm subtype emm43.4 with a pbp2x missense mutation (T553K) were detected. Minimum inhibitory concentrations (MICs) for ampicillin and amoxicillin were 8-fold higher, and the MIC for cefotaxime was 3-fold higher than for near-isogenic control isolates, consistent with a first step in developing ß-lactam resistance.

Immune reconstitution inflammatory syndrome associated with disseminated histoplasmosis and TNF-alpha inhibition.

Endemic fungal infections are a significant problem for patients on TNF-alpha inhibitors. Immune reconstitution inflammatory syndrome, IRIS, can present in patients with waning TNF-alpha inhibition and an endemic fungal infection. There may be a potential role that TNF-alpha inhibitors can play in mitigating IRIS related to disseminated endemic fungal infections.

Predictors of change in cognitive processing therapy for veterans in a residential PTSD treatment program.

OBJECTIVE: Cognitive processing therapy is an evidence-based treatment for posttraumatic stress disorder (PTSD); however, questions remain regarding variability in treatment response. METHOD: A total of 123 veterans participated in group-based cognitive processing therapy (CPT) in residential PTSD treatment. Change over time in PTSD symptoms was modeled as a function of selected demographic and clinical variables. RESULTS: PTSD checklist (PCL) scores decreased by an average of 1 point per session (standard deviation [SD] = 0.1). Initial PCL scores were predicted by the Beck Depression Inventory-II (γ01 = 0.25; standard error [SE] = 0.08), Insomnia Severity Index (γ02 = 0.53; SE = 0.15), and Infrequency (F) scale of the Minnesota Multiphasic Personality Inventory-2 (γ03 = 0.09; SE = 0.04). Rate of change was predicted by the Somatic Complaints (RC1) scale (γ11 = -0.03; SE = 0.01) and the Antisocial Behavior (RC4) scale (γ12 = 0.02; SE = 0.01). CONCLUSIONS: These results provide insight into characteristics that may influence degree of benefit received from group-based CPT.

Query expansion using MeSH terms for dataset retrieval: OHSU at the bioCADDIE 2016 dataset retrieval challenge.

Database URL: https://biocaddie.org/benchmark-data.

Red Cell Storage Duration Does Not Affect Outcome after Massive Blood Transfusion in Trauma and Nontrauma Patients: A Retrospective Analysis of 305 Patients.

BACKGROUND: Prolonged storage of packed red blood cells (PRBCs) may increase morbidity and mortality, and patients having massive transfusion might be especially susceptible. We therefore tested the hypothesis that prolonged storage increases mortality in patients receiving massive transfusion after trauma or nontrauma surgery. Secondarily, we considered the extent to which storage effects differ for trauma and nontrauma surgery. METHODS: We considered surgical patients given more than 10 units of PRBC within 24 hours and evaluated the relationship between mean PRBC storage duration and in-hospital mortality using multivariable logistic regression. Potential nonlinearities in the relationship were assessed via restricted cubic splines. The secondary hypothesis was evaluated by considering whether there was an interaction between the type of surgery (trauma versus nontrauma) and the effect of storage duration on outcomes. RESULTS: 305 patients were given a total of 8,046 units of PRBCs, with duration ranging from 8 to 36 days (mean ± SD: 22 ± 6 days). The odds ratio [95% confidence interval (CI)] for in-hospital mortality corresponding to a one-day in mean PRBC storage duration was 0.99 (0.95, 1.03, P = 0.77). The relationship did not differ for trauma and nontrauma patients (P = 0.75). Results were similar after adjusting for multiple potential confounders. CONCLUSIONS: Mortality after massive blood transfusion was no worse in patients transfused with PRBC stored for long periods. Trauma and nontrauma patients did not differ in their susceptibility to prolonged PRBC storage.

Implementation of a Medication Reconciliation Assistive Technology: A Qualitative Analysis.

Objective: To aid the implementation of a medication reconciliation process within a hybrid primary-specialty care setting by using qualitative techniques to describe the climate of implementation and provide guidance for future projects. Methods: Guided by McMullen et al's Rapid Assessment Process1, we performed semi-structured interviews prior to and iteratively throughout the implementation. Interviews were coded and analyzed using grounded theory2 and cross-examined for validity. Results: We identified five barriers and five facilitators that impacted the implementation. Facilitators identified were process alignment with user values, and motivation and clinical champions fostered by the implementation team rather than the administration. Barriers included a perceived limited capacity for change, diverging priorities, and inconsistencies in process standards and role definitions. Discussion: A more complete, qualitative understanding of existing barriers and facilitators helps to guide critical decisions on the design and implementation of a successful medication reconciliation process.

Improved recovery and identification of membrane proteins from rat hepatic cells using a centrifugal proteomic reactor.

Despite their importance in many biological processes, membrane proteins are underrepresented in proteomic analysis because of their poor solubility (hydrophobicity) and often low abundance. We describe a novel approach for the identification of plasma membrane proteins and intracellular microsomal proteins that combines membrane fractionation, a centrifugal proteomic reactor for streamlined protein extraction, protein digestion and fractionation by centrifugation, and high performance liquid chromatography-electrospray ionization-tandem MS. The performance of this approach was illustrated for the study of the proteome of ER and Golgi microsomal membranes in rat hepatic cells. The centrifugal proteomic reactor identified 945 plasma membrane proteins and 955 microsomal membrane proteins, of which 63 and 47% were predicted as bona fide membrane proteins, respectively. Among these proteins, >800 proteins were undetectable by the conventional in-gel digestion approach. The majority of the membrane proteins only identified by the centrifugal proteomic reactor were proteins with ≥ 2 transmembrane segments or proteins with high molecular mass (e.g. >150 kDa) and hydrophobicity. The improved proteomic reactor allowed the detection of a group of endocytic and/or signaling receptor proteins on the plasma membrane, as well as apolipoproteins and glycerolipid synthesis enzymes that play a role in the assembly and secretion of apolipoprotein B100-containing very low density lipoproteins. Thus, the centrifugal proteomic reactor offers a new analytical tool for structure and function studies of membrane proteins involved in lipid and lipoprotein metabolism.

Smad inhibition by the Ste20 kinase Misshapen.

The level of TGF-ß/bone morphogenetic protein (BMP) signaling through Smad is tightly regulated to ensure proper embryonic patterning and homeostasis. Here we show that Smad activation by TGF-ß/BMP is blocked by a highly conserved phosphorylation event in the α-helix 1 region of Smad [T312 in Drosophila Smad1 (MAD)]. α-helix 1 phosphorylation reduces Smad interaction with TGF-ß/BMP receptor kinase and affects all receptor-activated Smads except Smad3. Tissue culture and transgenic studies in Drosophila further demonstrate that the biological activity of MAD is repressed by T312 phosphorylation in vivo. Through RNAi screening of the kinome, we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation. Targeted expression of an active form of Msn in the wing imaginal disk disrupted activation of endogenous MAD by Dpp and expression of the Dpp/MAD target gene. Msn kinases belong to the Ste20 kinase family that has been shown to act as MAP kinase kinase kinase kinase (MAP4K). Our findings thus reveal a function of Msn independent of its impact on MAP kinase cascades. This Smad inhibition mechanism by Msn likely has important implications for development and disease.

Quantitative proteomic analysis of PCSK9 gain of function in human hepatic HuH7 cells.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis, mediating degradation of the liver low-density lipoprotein receptor (LDLR). In fact, gain- and loss-of-function PCSK9 variations in human populations associate with hyper- or hypo- cholesterolemia, respectively. Exactly how PCSK9 promotes degradation of the LDLR, the identity of the other biomolecules involved in this process, and the global effect of PCSK9 on other proteins has not been thoroughly studied. Here we employ stable isotope labeling with amino acids in cell culture (SILAC) to present the first quantitative, subcellular proteomic study of proteins affected by the stable overexpression of a gain-of-function PCSK9 membrane-bound chimera (PCSK9-V5-ACE2) in comparison to control, empty vector transfections in a human hepatocyte (HuH7) cell line. The expression level of 327 of 5790 peptides was modified by PCSK9-V5-ACE2 overexpression. Immunoblotting was carried out for the control transferrin receptor, shown to be unaffected in cells overexpressing PCSK9-V5-ACE2, thus validating our SILAC results. We also used immunoblotting to confirm the novel SILAC results of up- and down-regulation of several proteins in cells overexpressing PCSK9-V5-ACE2. Moreover, we documented the novel down-regulation of the EH domain binding protein-1 (EHBP1) in a transgenic PCSK9 mouse model and its up-regulation in a PCSK9 knockout mouse model.

Analysis of the subcellular phosphoproteome using a novel phosphoproteomic reactor.

Protein phosphorylation is an important post-translational modification involved in the regulation of many cellular processes. Mass spectrometry has been successfully used to identify protein phosphorylation in specific pathways and for global phosphoproteomic analysis. However, phosphoproteomics approaches do not evaluate the subcellular localization of the phosphorylated forms of proteins, which is an important factor for understanding the roles of protein phosphorylation on a global scale. The in-depth mapping of protein phosphorylation at the subcellular level necessitates the development of new methods capable of specifically and efficiently enriching phosphopeptides from highly complex samples. Here, we report a novel microfluidic device called the phosphoproteomic reactor that combines efficient processing of proteins followed by phosphopeptide enrichment by Ti-IMAC. To illustrate the potential of this novel technology, we mapped the phosphoproteins in subcellular organelles of liver cells. Fifteen subcellular fractions from liver cell cultures were processed on the phosphoproteomic reactor in combination with nano-LC-MS/MS analysis. We identified thousands of phosphorylation sites in over 600 phosphoproteins in different organelles using minute amounts of starting material. Overall, this approach provides a new avenue for studying the phosphoproteome of the subcellular organelles.

Increased production and secretion of HGF alpha-chain and an antagonistic HGF fragment in a human breast cancer progression model.

Invasive human breast carcinomas frequently coexpress increased hepatocyte growth factor (HGF) and its receptor Met, suggesting that establishment of an autocrine HGF loop is important in malignant disease. This study examines the expression patterns of HGF and Met activation during tumorigenesis and metastasis using a MCF10A-based model of Ha-Ras-induced human breast cancer progression. Deregulation of cadherin-based cell-cell adhesions, decreased expression of cytokeratins 8/18 and increased activity of matrix metalloproteinases such as MMP-2 occurs in premalignant and malignant (metastatic) cell lines compared to the parental nonmalignant cell line. Compared to the benign parent cell line, premalignant and malignant cell lines exhibit increased secretion of full length HGF alpha-chain and elevated Met tyrosine phosphorylation in complete medium. Interestingly, the premalignant and malignant cells also secrete a approximately 55 kDa HGF fragment. Epitope mapping of the approximately 55 kDa HGF fragment supports the presence of the N-terminal domain of the HGF alpha-chain with a truncation in the C-terminal domain. The approximately 55 kDa HGF fragment shows mobility in SDS-PAGE faster than HGF alpha-chain, but slightly slower than NK4, a previously established full antagonist of HGF. The separated approximately 55 kDa HGF fragment binds to animmobilized Met-IgG fusion protein, and inhibits both HGF/Met-IgG binding and HGF-induced Met-tyrosine phosphorylation. These results are the first demonstration of an antagonistic approximately 55 kDa HGF fragment secreted during breast carcinoma progression, which may have a negative regulatory effect on HGF signaling in premalignant breast epithelial cells.

Performance evaluation of the ADVIA Centaur anti-HBe and HBeAg assays.

BACKGROUND: Detection of HBeAg and anti-HBe is valuable for the evaluation and therapeutic management of hepatitis B infection. OBJECTIVES: To determine the clinical performance of the newly CE-approved(a) HBeAg and anti-HBe assays on the fully automated, random access ADVIA Centaur immunoassay system. STUDY DESIGN: Patient samples collected at two sites were used to compare the ADVIA Centaur assays to Abbott AxSYM assays. Consensus of discordant results was reached using Roche Elecsys assays. Additionally, two well-characterized seroconversion panels were evaluated. RESULTS: The ADVIA Centaur HBeAg assay sensitivity was 100% and specificity was 99.5%. The ADVIA Centaur anti-HBe assay sensitivity was 100% and the resolved specificity was 98.2%. Fewer samples required retesting with the ADVIA Centaur assays than with the AxSYM. In two well-characterized seroconversion panels, the ADVIA Centaur anti-HBe assay detected anti-HBe 20-25 days earlier than the AxSYM assay; the ADVIA Centaur and AxSYM HBeAg assays detected HBe reactivity on the same day. CONCLUSIONS: The ADVIA Centaur HBeAg and anti-HBe assays demonstrated good sensitivity and specificity, and thus are suitable for clinical use. Their novel algorithms require reduced retesting, suggesting these assays may be more cost effective.

Inhibition by copper(II) binding of hepatocyte growth factor (HGF) interaction with its receptor Met and blockade of HGF/Met function.

Overexpression of hepatocyte growth factor (HGF) and its receptor Met often occurs in carcinoma cells, leading to establishment of an HGF/Met autocrine loop. Therefore, disruption of the HGF/Met autocrine loop may lead to down-regulation of tumorigenesis. To study the HGF/Met interaction, we have developed a cell-free system to detect HGF binding to a Met fusion protein, Met-IgG, using a modified enzyme-linked immunosorbent assay methodology. Since we previously showed that HGF can be purified by copper(II) affinity chromatography, we further explored the effect of copper(II) on the HGF/Met interaction. The divalent metal cations copper(II) and zinc(II) significantly inhibited HGF binding to immobilized Met-IgG with IC(50) values of 230-270 microM, respectively, whereas manganese(II) and magnesium(II) were less inhibitory with 20-60-fold higher IC(50) values. Incubation of 1 mM copper(II) with HGF resulted in nondenaturing and denaturing gel-mobility shifts, indicating that copper(II) binds directly to HGF. This interaction occurs at the N terminus of HGF, as incubation of 1 mM copper(II) with both HGF and the HGF derivative NK1 yielded similar results on SDS-PAGE. HGF-induced activation of Met and cell scattering were inhibited upon addition of HGF in the presence of 1 mM and 500 microM copper(II), respectively. Chemical protonation with diethyl pyrocarbonate of HGF histidine residues impeded the ability of 500 microM copper(II) to inhibit the binding of HGF to immobilized Met-IgG. Based on the NK1 domain structure, we propose that copper(II) may interact with HGF via the histidine residues in either N-terminal or kringle domains. The inhibition of HGF/Met interaction and subsequent downstream cellular functions may be through direct interference by copper(II), such as a change in charge or an induced local conformational change. This putative copper(II) binding domain may be the basis for developing potential inhibitors of HGF/Met binding and downstream functions and could lead to novel strategies for anti-cancer treatment.

Quantitative evaluation of the contribution of weak lysine-binding sites present within apolipoprotein(a) kringle IV types 6-8 to lipoprotein(a) assembly.

During lipoprotein(a) (Lp(a)) assembly, non-covalent interactions between apolipoprotein(a) (apo(a)) and low density lipoprotein precede specific disulfide bond formation. Studies have shown that the non-covalent step involves an interaction between the weak lysine-binding sites (WLBS) present within each of apo(a) kringle IV types 6, 7, and 8 (KIV(6-8)), and two lysine residues (Lys(680) and Lys(690)) within the NH(2) terminus of the apolipoprotein B-100 (apoB) component of low density lipoprotein. In the present study, we introduced single point mutations (E56G) into each of the WLBS present in apo(a) KIV(6-8) and expressed these mutations in the context of a 17-kringle (17K) recombinant apo(a) variant. Single mutations that disrupt the WLBS in KIV(6), KIV(7), and KIV(8), as well as mutants that disrupt the WLBS in both KIV(6) and KIV(7), or both KIV(7) and KIV(8), were assessed for their ability to form non-covalent and covalent Lp(a) complexes. Our results demonstrate that both apo(a) KIV(7) and KIV(8), but not KIV(6), are required for maximally efficient non-covalent and covalent Lp(a) assembly. Single mutations in the WLBS of KIV(7) or KIV(8) resulted in a 3-fold decrease in the affinity of 17K recombinant apo(a) for apoB, and a 20% reduction in the rate of covalent Lp(a) formation. Tandem mutations in the WLBS in both KIV(7) and KIV(8) resulted in a 13-fold reduction in the binding affinity between apo(a) and apoB, and a 75% reduction in the rate of the covalent step of Lp(a) formation. We also showed that KIV(7) and KIV(8) specifically bind with high affinity to apoB-derived peptides containing Lys(690) or Lys(680), respectively. Taken together, our data demonstrate that specific interactions between apo(a) KIV(7) and KIV(8) and Lys(680) and Lys(690) in apoB mediate a high affinity non-covalent interaction between apo(a) and low density lipoprotein, which dictates the efficiency of covalent Lp(a) formation.

Intramuscular low-grade myxoid neoplasm with recurrent potential (cellular myxoma) of the lower extremity: case report with cytohistologic correlation and review of the literature.

"Low-grade myxoid neoplasm with recurrent potential" (cellular myxoma) is a term recently used to describe a subset of soft tissue lesions with histology intermediate between intramuscular myxoma and low-grade myxofibrosarcoma or myxoid malignant fibrous histiocytoma (MFH), while resembling a deeper counterpart of superficial angiomyxoma. Their distinctive biological behavior is characterized by the potential to recur locally, in contrast to intramuscular myxoma, while having no potential to advance in grade or metastasize when compared to low-grade myxofibrosarcoma. We present a cytohistological correlation for an intramuscular location of such a tumor in the lower extremity of a 49-yr-old male.