Case Studies of Performance Based Logistics in the Military: International Lessons Learned

Performance-based logistics (PBL) represents a support strategy for weapon systems and manifests in contracts that focus on the delivery of outcome performance not process outputs. Despite the high research interest in the underlying theory, only few studies address the question how PBL is actually used. Some quantitative studies have researched this question by evaluating the perceptions of involved management people. Other data, such as prices, contract terms, or performance indicators, are often only available in form of qualitative case studies. Therefore, the purpose of this research is to report on a number of PBL cases and to provide a holistic view on their characteristics and the effectiveness as a support strategy. The analysis identified a high number of more than 100 cases that are reported in the literature. Filter methods are used to identify heterogenous case examples. The chosen cases are described and analyzed considering contract terms, price mechanisms and performance indicators. The findings show the wide range of PBL applications in international weapon system support. This guides this research to a number of research and practical propositions

Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression

G(s) protein-coupled receptors regulate many vital body functions by activation of cAMP response elements (CRE) via cAMP-dependent kinase A (PKA)-mediated phosphorylation of the CRE binding protein (CREB). Melanocortin 4 receptors (MC4R) are prototypical G(s)-coupled receptors that orchestrate the hypothalamic control of food-intake and metabolism. Remarkably, the significance of PKA for MC4R-induced CRE-dependent transcription in hypothalamic cells has not been rigorously interrogated yet. In two hypothalamic cell lines, we observed that blocking PKA activity had only weak or no effects on reporter gene expression. In contrast, inhibitors of exchange factors directly activated by cAMP-1/2 (EPAC-1/2) mitigated MC4R-induced CRE reporter activation and mRNA induction of the CREB-dependent genes c-fos and thyrotropin-releasing hormone. Furthermore, we provide first evidence that extracellular-regulated kinases-1/2 (ERK-1/2) activated by EPACs and not PKA are the elusive CREB kinases responsible for MC4R-induced CREB/CRE activation in hypothalamic cells. Overall, these data emphasize the pivotal role of EPACs rather than PKA in hypothalamic gene expression elicited by a prototypical Gs-coupled receptor

Regulation of Nucleotide Excision Repair by UV-DDB: Prioritization of Damage Recognition to Internucleosomal DNA

This study reveals the molecular mechanism by which the nucleotide excision repair protein DDB2 prioritises excision of UV-induced DNA lesions in the nucleosome landscape

Non-Invasive Assessment of Intra-Abdominal Pressure Using Ultrasound Guided Tonometry - a Proof-of-Concept Study.

BACKGROUND Intra-abdominal hypertension jeopardizes abdominal organ perfusion and venous return. Contemporary recognition of elevated intra-abdominal pressure (IAP) plays a crucial role in reducing mortality and morbidity. We evaluated ultrasound guided tonometry in this context hypothesizing that the vertical chamber diameter of this device inversely correlates with intra-abdominal pressure. METHODS IAP was increased in six 5 mmHg steps to 40 mmHg by instillation of normal saline into the peritoneal cavity of eight anesthetized pigs. Liver and renal blood flows (ultrasound transit time), intra-vesical, intra-peritoneal and end-inspiratory plateau pressures were recorded. For ultrasound-based assessment of intra-abdominal pressure (ultrasound guided tonometry), a pressure transducing, compressible chamber was fixed at the tip of a linear ultrasound probe, and the system was applied on the abdominal wall using different pre-determined levels of external pressure. At each IAP level (reference: intra-vesical pressure), two investigators measured the vertical diameter of this chamber. RESULTS All abdominal flows decreased (by 39% to 58%), and end-inspiratory plateau pressure increased from 15 mbar (14-17 mbar) to 38 mbar (33-42 mbar) (median, range) with increasing IAP (all p < 0.01). Vertical chamber diameter decreased from 14.9 (14.6-15.2) mm to12.8 (12.4-13.4) mm with increasing IAP. Coefficients of variations between and within observers regarding change of the vertical tonometry chamber diameter were small (all < 4%), and the results were independent of the externally applied pressure level on the ultrasound probe. Correlation of IAP and vertical pressure chamber distance was highly significant (r: -1, p: 0.0004). Ultrasound guided tonometry could discriminate between normal (baseline) pressure and 15 mmHg, between 15 and 25mmHg) and between 25 and 40 mmHg IAP (all p≤0.18). Similar results were obtained for end-inspiratory plateau pressures. CONCLUSIONS In our model, values obtained by ultrasound guided tonometry correlated significantly with intra-abdominal pressures. The method was able to discriminate between normal, moderately and markedly increased IAP values

Non-Invasive Assessment of Intra-Abdominal Pressure Using Ultrasound Guided Tonometry - a Proof-of-Concept Study.

BACKGROUND Intra-abdominal hypertension jeopardizes abdominal organ perfusion and venous return. Contemporary recognition of elevated intra-abdominal pressure (IAP) plays a crucial role in reducing mortality and morbidity. We evaluated ultrasound guided tonometry in this context hypothesizing that the vertical chamber diameter of this device inversely correlates with intra-abdominal pressure. METHODS IAP was increased in six 5 mmHg steps to 40 mmHg by instillation of normal saline into the peritoneal cavity of eight anesthetized pigs. Liver and renal blood flows (ultrasound transit time), intra-vesical, intra-peritoneal and end-inspiratory plateau pressures were recorded. For ultrasound-based assessment of intra-abdominal pressure (ultrasound guided tonometry), a pressure transducing, compressible chamber was fixed at the tip of a linear ultrasound probe, and the system was applied on the abdominal wall using different pre-determined levels of external pressure. At each IAP level (reference: intra-vesical pressure), two investigators measured the vertical diameter of this chamber. RESULTS All abdominal flows decreased (by 39% to 58%), and end-inspiratory plateau pressure increased from 15 mbar (14-17 mbar) to 38 mbar (33-42 mbar) (median, range) with increasing IAP (all p < 0.01). Vertical chamber diameter decreased from 14.9 (14.6-15.2) mm to12.8 (12.4-13.4) mm with increasing IAP. Coefficients of variations between and within observers regarding change of the vertical tonometry chamber diameter were small (all < 4%), and the results were independent of the externally applied pressure level on the ultrasound probe. Correlation of IAP and vertical pressure chamber distance was highly significant (r: -1, p: 0.0004). Ultrasound guided tonometry could discriminate between normal (baseline) pressure and 15 mmHg, between 15 and 25mmHg) and between 25 and 40 mmHg IAP (all p≤0.18). Similar results were obtained for end-inspiratory plateau pressures. CONCLUSIONS In our model, values obtained by ultrasound guided tonometry correlated significantly with intra-abdominal pressures. The method was able to discriminate between normal, moderately and markedly increased IAP values

Performance-based contracting in business markets

The aim of this Special Issue is to advance our understanding of performance-based contracting (PBC) in business markets. PBC has the potential for aligning incentives among buyers and sellers and fostering innovation. This paper critically reflects on extant research in order to develop a systematic knowledge map of PBC research. On that basis four major research gaps are identified and addressed, drawing out specific avenues for further PBC research. The knowledge map is also used to illustrate the focus and main arguments of the articles featuring in this Special Issue

Investigating the Concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC

Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: One step forward, and one step back?

A group of 160 patients with primary glioblastoma treated with radiotherapy and temozolomide was analyzed for the impact of O6-methly-guanly-methyl-transferase (MGMT)-promoter methylation as well as isocitrate dehydrogenase (IDH)1-mutational status. Unexpectedly, overall survival or progression-free survival were not longer in the group with methylated MGMT-promoter as compared to patients without that methylation. IDH-1 mutations were significantly associated with increased overall survival

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419)

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma